bims-mitdis 2024-10-13 papers

bims-mitdis

Biomed News

on Mitochondrial disorders

Issue of 2024‒10‒13
forty-two papers selected by
Catalina Vasilescu, Helmholz Munich

DELE1 maintains muscle proteostasis to promote growth and survival in mitochondrial myopathy.
Selection promotes age-dependent degeneration of the mitochondrial genome.
Taurine hypomodification underlies mitochondrial tRNATrp-related genetic diseases.
Compensatory activity of the PC-ME1 metabolic axis underlies differential sensitivity to mitochondrial complex I inhibition.
Biallelic variants in DAP3 result in reduced assembly of the mitoribosomal small subunit with altered intrinsic and extrinsic apoptosis and a Perrault syndrome-spectrum phenotype.
Loss of mitochondrial Ca2+ response and CaMKII/ERK activation by LRRK2R1441G mutation correlate with impaired depolarization-induced mitophagy.
Ribosomes hibernate on mitochondria during cellular stress.
Disease models of Leigh syndrome: From yeast to organoids.
CD38 and the mitochondrial calcium uniporter contribute to age-related hematopoietic stem cell dysfunction.
Clinico-Radiological and Genotypic Spectrum of Nuclear Mitochondriopathies.
Mitochondrial RNA maturation.
[Taurine for Mitochondrial Diseases].
Coordinating BNIP3/NIX-mediated mitophagy in space and time.
Nuclear compensatory evolution driven by mito-nuclear incompatibilities.
Reduced protein kinase C delta in a high molecular weight complex in mitochondria and elevated creatine uptake into Barth syndrome B lymphoblasts.
Effect of alternative oxidase (AOX) expression on mouse cerebral mitochondria bioenergetics.
NEK10 kinase ablation affects mitochondrial morphology, function and protein phosphorylation status.
A germline-to-soma signal triggers an age-related decline of mitochondrial stress response.
Mitochondrial Extracellular Vesicles (mitoEVs): Emerging mediators of cell-to-cell communication in health, aging and age-related diseases.
Mitochondrial apolipoprotein MIC26 is a metabolic rheostat regulating central cellular fuel pathways.
ER-mitochondria distance is a critical parameter for efficient mitochondrial Ca2+ uptake and oxidative metabolism.
Targeting Mitochondria: Influence of Metabolites on Mitochondrial Heterogeneity.
Metabolic regulation of mitochondrial morphologies in pancreatic beta cells: coupling of bioenergetics and mitochondrial dynamics.
Dynamic death decisions: How mitochondrial dynamics shape cellular commitment to apoptosis and ferroptosis.
CEAM is a mitochondrial-localized, amyloid-like motif-containing microprotein expressed in human cardiomyocytes.
The intricacies of mitochondrial calcium and enzyme regulation in liver metabolism.
Sex-specific decline in prefrontal cortex mitochondrial bioenergetics in aging baboons correlates with walking speed.
Inducible and reversible SOD2 knockdown in mouse skeletal muscle drives impaired pyruvate oxidation and reduced metabolic flexibility.
Loss of atrial natriuretic peptide signaling causes insulin resistance, mitochondrial dysfunction, and low endurance capacity.
Mitochondrial topoisomerase I (Top1MT) prevents the onset of metabolic dysfunction-associated steatohepatitis (MASH) in mice.
Calcium signaling in mitochondrial intermembrane space.
Germline loss diminishes somatic mitochondria but confers preservation of respiratory function during aging and hypothermia.
Drp1 acetylation mediated by CDK5-AMPK-GCN5L1 axis promotes cerebral ischemic injury via facilitating mitochondrial fission.
Endonuclease G is dispensable for sperm mitochondrial DNA elimination during spermatogenesis in mice.
A proteogenomic atlas of the human neural retina.
Increased ketone levels as a key magnetic resonance spectroscopic findings during acute exacerbation in ECHS1-related Leigh syndrome.
One-step nanoscale expansion microscopy reveals individual protein shapes.
Mitochondrial MOF regulates energy metabolism in heart failure via ATP5B hyperacetylation.
TARS2 c.470 C > G is a chinese-specific founder mutation in three unrelated families with mitochondrial encephalomyopathy.
Imaging and proteomics toolkits for studying organelle contact sites.
Natural variation in age-related dopamine neuron degeneration is glutathione dependent and linked to life span.
FGF21 inhibits ferroptosis caused by mitochondrial damage to promote the repair of peripheral nerve injury.

EMBO J. 2024 Oct 08.

DELE1 maintains muscle proteostasis to promote growth and survival in mitochondrial myopathy.

Hsin-Pin Lin, Jennifer D Petersen, Alexandra J Gilsrud, Angelo Madruga, Theresa M D'Silva, Xiaoping Huang, Mario K Shammas, Nicholas P Randolph, Kory R Johnson, Yan Li, Drew R Jones, Michael E Pacold, Derek P Narendra.

  Mitochondrial dysfunction causes devastating disorders, including mitochondrial myopathy, but how muscle senses and adapts to mitochondrial dysfunction is not well understood. Here, we used diverse mouse models of mitochondrial myopathy to show that the signal for mitochondrial dysfunction originates within mitochondria. The mitochondrial proteins OMA1 and DELE1 sensed disruption of the inner mitochondrial membrane and, in response, activated the mitochondrial integrated stress response (mt-ISR) to increase the building blocks for protein synthesis. In the absence of the mt-ISR, protein synthesis in muscle was dysregulated causing protein misfolding, and mice with early-onset mitochondrial myopathy failed to grow and survive. The mt-ISR was similar following disruptions in mtDNA maintenance (Tfam knockout) and mitochondrial protein misfolding (CHCHD10 G58R and S59L knockin) but heterogenous among mitochondria-rich tissues, with broad gene expression changes observed in heart and skeletal muscle and limited changes observed in liver and brown adipose tissue. Taken together, our findings identify that the DELE1 mt-ISR mediates a similar response to diverse forms of mitochondrial stress and is critical for maintaining growth and survival in early-onset mitochondrial myopathy.

Keywords:  Mitochondria Unfolded Protein Response (mt-UPR); Mitochondrial Disorders; Mitohormesis; Mitonuclear Communication; Mitophagy

DOI:  https://doi.org/10.1038/s44318-024-00242-x
bioRxiv. 2024 Sep 28. pii: 2024.09.27.615276. [Epub ahead of print]

Selection promotes age-dependent degeneration of the mitochondrial genome.

Ekaterina Korotkevich, Daniel N Conrad, Zev J Gartner, Patrick H O'Farrell.

Somatic mutations in mitochondrial genomes (mtDNA) accumulate exponentially during aging. Using single cell sequencing, we characterize the spectrum of age-accumulated mtDNA mutations in mouse and human liver and identify directional forces that accelerate the accumulation of mutations beyond the rate predicted by a neutral model. "Driver" mutations that give genomes a replicative advantage rose to high cellular abundance and carried along "passenger" mutations, some of which are deleterious. In addition, alleles that alter mtDNA-encoded proteins selectively increased in abundance overtime, strongly supporting the idea of a "destructive" selection that favors genomes lacking function. Overall, this combination of selective forces acting in hepatocytes promotes somatic accumulation of mutations in coding regions of mtDNA that are otherwise conserved in evolution. We propose that these selective processes could contribute to the population prevalence of mtDNA mutations, accelerate the course of heteroplasmic mitochondrial diseases and promote age-associated erosion of the mitochondrial genome.

DOI: https://doi.org/10.1101/2024.09.27.615276
Nucleic Acids Res. 2024 Oct 09. pii: gkae854. [Epub ahead of print]

Taurine hypomodification underlies mitochondrial tRNATrp-related genetic diseases.

Jia-Li Lu, Yichen Dai, Kunqian Ji, Gui-Xin Peng, Hong Li, Chuanzhu Yan, Bin Shen, Xiao-Long Zhou.

Escherichia coli MnmE and MnmG form a complex (EcMnmEG), generating transfer RNA (tRNA) 5-carboxymethylaminomethyluridine (cmnm5U) modification. Both cmnm5U and equivalent 5-taurinomethyluridine (τm5U, catalyzed by homologous GTPBP3 and MTO1) are found at U34 in several human mitochondrial tRNAs (hmtRNAs). Certain mitochondrial DNA (mtDNA) mutations, including m.3243A > G in tRNALeu(UUR) and m.8344A > G in tRNALys, cause genetic diseases, partially due to τm5U hypomodification. However, whether other mtDNA variants in different tRNAs cause a defect in τm5U biogenesis remains unknown. Here, we purified naturally assembled EcMnmEG from E. coli. Notably, EcMnmEG was able to incorporate both cmnm5U and τm5U into hmtRNATrp (encoded by MT-TW), providing a valuable basis for directly monitoring the effects of mtDNA mutations on U34 modification. In vitro, several clinical hmtRNATrp pathogenic mutations caused U34 hypomodification. A patient harboring an m.5541C > T mutation exhibited hmtRNATrp τm5U hypomodification. Moreover, using mtDNA base editing, we constructed two cell lines carrying m.5532G > A or m.5545C > T mutations, both of which exhibited hmtRNATrp τm5U hypomodification. Taurine supplementation improved mitochondrial translation in patient cells. Our findings describe the third hmtRNA species with mutation-related τm5U-hypomodification and provide new insights into the pathogenesis and intervention strategy for hmtRNATrp-related genetic diseases.

DOI: https://doi.org/10.1093/nar/gkae854
Nat Commun. 2024 Oct 07. 15(1): 8682

Compensatory activity of the PC-ME1 metabolic axis underlies differential sensitivity to mitochondrial complex I inhibition.

Lucia Del Prado, Myriam Jaraíz-Rodríguez, Mauro Agro, Marcos Zamora-Dorta, Natalia Azpiazu, Manuel Calleja, Mario Lopez-Manzaneda, Jaime de Juan-Sanz, Alba Fernández-Rodrigo, José A Esteban, Mònica Girona, Albert Quintana, Eduardo Balsa.

Deficiencies in the electron transport chain (ETC) lead to mitochondrial diseases. While mutations are distributed across the organism, cell and tissue sensitivity to ETC disruption varies, and the molecular mechanisms underlying this variability remain poorly understood. Here we show that, upon ETC inhibition, a non-canonical tricarboxylic acid (TCA) cycle upregulates to maintain malate levels and concomitant production of NADPH. Our findings indicate that the adverse effects observed upon CI inhibition primarily stem from reduced NADPH levels, rather than ATP depletion. Furthermore, we find that Pyruvate carboxylase (PC) and ME1, the key mediators orchestrating this metabolic reprogramming, are selectively expressed in astrocytes compared to neurons and underlie their differential sensitivity to ETC inhibition. Augmenting ME1 levels in the brain alleviates neuroinflammation and corrects motor function and coordination in a preclinical mouse model of CI deficiency. These studies may explain why different brain cells vary in their sensitivity to ETC inhibition, which could impact mitochondrial disease management.

DOI: https://doi.org/10.1038/s41467-024-52968-1
medRxiv. 2024 Aug 21. pii: 2024.08.19.24312079. [Epub ahead of print]

Biallelic variants in DAP3 result in reduced assembly of the mitoribosomal small subunit with altered intrinsic and extrinsic apoptosis and a Perrault syndrome-spectrum phenotype.

DDD Study

  The mitoribosome synthesizes 13 protein subunits of the oxidative phosphorylation system encoded by the mitochondrial genome. The mitoribosome is composed of 12S rRNA, 16S rRNA and 82 mitoribosomal proteins encoded by nuclear genes. To date, variants in 12 genes encoding mitoribosomal proteins are associated with rare monogenic disorders, and frequently show combined oxidative phosphorylation deficiency. Here, we describe five unrelated individuals with biallelic variants in the DAP3 nuclear gene encoding mitoribosomal small subunit 29 (MRPS29), with variable clinical presentations ranging from Perrault syndrome (sensorineural hearing loss and ovarian insufficiency) to an early childhood neurometabolic phenotype. Assessment of respiratory chain function and proteomic profiling of fibroblasts from affected individuals demonstrated reduced MRPS29 protein levels, and consequently decreased levels of additional protein components of the mitoribosomal small subunit, associated with a combined complex I and IV deficiency. Lentiviral transduction of fibroblasts from affected individuals with wild-type DAP3 cDNA increased DAP3 mRNA expression, and partially rescued protein levels of MRPS7, MRPS9 and complex I and IV subunits, demonstrating the pathogenicity of the DAP3 variants. Protein modelling suggested that DAP3 disease-associated missense variants can impact ADP binding, and in vitro assays demonstrated DAP3 variants can consequently reduce both intrinsic and extrinsic apoptotic sensitivity, DAP3 thermal stability and DAP3 GTPase activity. Our study presents genetic and functional evidence that biallelic variants in DAP3 result in a multisystem disorder of combined oxidative phosphorylation deficiency with pleiotropic presentations, consistent with mitochondrial dysfunction.

Keywords:  DAP3; MRPS29; Perrault syndrome; leukodystrophy; mitochondria; mitoribosomal small subunit; mitoribosome; ovarian insufficiency; rare disease; sensorineural hearing loss

DOI:  https://doi.org/10.1101/2024.08.19.24312079
Cell Commun Signal. 2024 Oct 10. 22(1): 485

Loss of mitochondrial Ca2+ response and CaMKII/ERK activation by LRRK2R1441G mutation correlate with impaired depolarization-induced mitophagy.

Eunice Eun-Seo Chang, Huifang Liu, Zoe Yuen-Kiu Choi, Yasine Malki, Steffi Xi-Yue Zhang, Shirley Yin-Yu Pang, Michelle Hiu-Wai Kung, David B Ramsden, Shu-Leong Ho, Philip Wing-Lok Ho.

  BACKGROUND: Stress-induced activation of ERK/Drp1 serves as a checkpoint in the segregation of damaged mitochondria for autophagic clearance (mitophagy). Elevated cytosolic calcium (Ca2+) activates ERK, which is pivotal to mitophagy initiation. This process is altered in Parkinson's disease (PD) with mutations in leucine-rich repeat kinase 2 (LRRK2), potentially contributing to mitochondrial dysfunction. Pathogenic LRRK2 mutation is linked to dysregulated cellular Ca2+ signaling but the mechanism involved remains unclear.METHODS: Mitochondrial damages lead to membrane depolarization. To investigate how LRRK2 mutation impairs cellular response to mitochondrial damages, mitochondrial depolarization was induced by artificial uncoupler (FCCP) in wild-type (WT) and LRRK2R1441G mutant knockin (KI) mouse embryonic fibroblasts (MEFs). The resultant cytosolic Ca2+ flux was assessed using live-cell Ca2+ imaging. The role of mitochondria in FCCP-induced cytosolic Ca2+ surge was confirmed by co-treatment with the mitochondrial sodium-calcium exchanger (NCLX) inhibitor. Cellular mitochondrial quality and function were evaluated by Seahorse™ real-time cell metabolic analysis, flow cytometry, and confocal imaging. Mitochondrial morphology was visualized using transmission electron microscopy (TEM). Activation (phosphorylation) of stress response pathways were assessed by immunoblotting.
RESULTS: Acute mitochondrial depolarization induced by FCCP resulted in an immediate cytosolic Ca2+ surge in WT MEFs, mediated predominantly via mitochondrial NCLX. However, such cytosolic Ca2+ response was abolished in LRRK2 KI MEFs. This loss of response in KI was associated with impaired activation of Ca2+/calmodulin-dependent kinase II (CaMKII) and MEK, the two upstream kinases of ERK. Treatment of LRRK2 inhibitor did not rescue this phenotype indicating that it was not caused by mutant LRRK2 kinase hyperactivity. KI MEFs exhibited swollen mitochondria with distorted cristae, depolarized mitochondrial membrane potential, and reduced mitochondrial Ca2+ store and mitochondrial calcium uniporter (MCU) expression. These mutant cells also exhibited lower cellular ATP: ADP ratio albeit higher basal respiration than WT, indicating compensation for mitochondrial dysfunction. These defects may hinder cellular stress response and signals to Drp1-mediated mitophagy, as evident by impaired mitochondrial clearance in the mutant.
CONCLUSIONS: Pathogenic LRRK2R1441G mutation abolished mitochondrial depolarization-induced Ca2+ response and impaired the basal mitochondrial clearance. Inherent defects from LRRK2 mutation have weakened the cellular ability to scavenge damaged mitochondria, which may further aggravate mitochondrial dysfunction and neurodegeneration in PD.

Keywords:  Calcium-dependent pathways; Cellular stress response; LRRK2 mutation; Mitochondrial dysfunction; Mitophagy; NCLX; Parkinson disease

DOI:  https://doi.org/10.1186/s12964-024-01844-y
Nat Commun. 2024 Oct 08. 15(1): 8666

Ribosomes hibernate on mitochondria during cellular stress.

Olivier Gemin, Maciej Gluc, Higor Rosa, Michael Purdy, Moritz Niemann, Yelena Peskova, Simone Mattei, Ahmad Jomaa.

Cell survival under nutrient-deprived conditions relies on cells' ability to adapt their organelles and rewire their metabolic pathways. In yeast, glucose depletion induces a stress response mediated by mitochondrial fragmentation and sequestration of cytosolic ribosomes on mitochondria. This cellular adaptation promotes survival under harsh environmental conditions; however, the underlying mechanism of this response remains unknown. Here, we demonstrate that upon glucose depletion protein synthesis is halted. Cryo-electron microscopy structure of the ribosomes show that they are devoid of both tRNA and mRNA, and a subset of the particles depicted a conformational change in rRNA H69 that could prevent tRNA binding. Our in situ structural analyses reveal that the hibernating ribosomes tether to fragmented mitochondria and establish eukaryotic-specific, higher-order storage structures by assembling into oligomeric arrays on the mitochondrial surface. Notably, we show that hibernating ribosomes exclusively bind to the outer mitochondrial membrane via the small ribosomal subunit during cellular stress. We identify the ribosomal protein Cpc2/RACK1 as the molecule mediating ribosomal tethering to mitochondria. This study unveils the molecular mechanism connecting mitochondrial stress with the shutdown of protein synthesis and broadens our understanding of cellular responses to nutrient scarcity and cell quiescence.

DOI: https://doi.org/10.1038/s41467-024-52911-4
J Inherit Metab Dis. 2024 Oct 09.

Disease models of Leigh syndrome: From yeast to organoids.

Marie-Thérèse Henke, Alessandro Prigione, Markus Schuelke.

  Leigh syndrome (LS) is a severe mitochondrial disease that results from mutations in the nuclear or mitochondrial DNA that impairs cellular respiration and ATP production. Mutations in more than 100 genes have been demonstrated to cause LS. The disease most commonly affects brain development and function, resulting in cognitive and motor impairment. The underlying pathogenesis is challenging to ascertain due to the diverse range of symptoms exhibited by affected individuals and the variability in prognosis. To understand the disease mechanisms of different LS-causing mutations and to find a suitable treatment, several different model systems have been developed over the last 30 years. This review summarizes the established disease models of LS and their key findings. Smaller organisms such as yeast have been used to study the biochemical properties of causative mutations. Drosophila melanogaster, Danio rerio, and Caenorhabditis elegans have been used to dissect the pathophysiology of the neurological and motor symptoms of LS. Mammalian models, including the widely used Ndufs4 knockout mouse model of complex I deficiency, have been used to study the developmental, cognitive, and motor functions associated with the disease. Finally, cellular models of LS range from immortalized cell lines and trans-mitochondrial cybrids to more recent model systems such as patient-derived induced pluripotent stem cells (iPSCs). In particular, iPSCs now allow studying the effects of LS mutations in specialized human cells, including neurons, cardiomyocytes, and even three-dimensional organoids. These latter models open the possibility of developing high-throughput drug screens and personalized treatments based on defined disease characteristics captured in the context of a defined cell type. By analyzing all these different model systems, this review aims to provide an overview of past and present means to elucidate the complex pathology of LS. We conclude that each approach is valid for answering specific research questions regarding LS, and that their complementary use could be instrumental in finding treatment solutions for this severe and currently untreatable disease.

Keywords:  Leigh syndrome; animal models; disease modeling; mitochondrial diseases; organoids; phenotyping; pluripotent stem cells

DOI:  https://doi.org/10.1002/jimd.12804
Immunometabolism (Cobham). 2024 Oct;6(4): e00048

CD38 and the mitochondrial calcium uniporter contribute to age-related hematopoietic stem cell dysfunction.

Connor S R Jankowski, Thomas Weichhart.

  Hematopoietic stem cells (HSCs) are the multipotent progenitors of all immune cells. During aging, their regenerative capacity decreases for reasons that are not well understood. Recently, Song et al investigated the roles of two metabolic proteins in age-related HSC dysfunction: CD38 (a membrane-bound NADase) and the mitochondrial calcium uniporter that transports calcium into the mitochondrial matrix. They found that the interplay between these proteins is deranged in aged HSCs, contributing to their diminished renewal capacity. These findings implicate compromised nicotinamide adenine dinucleotide metabolism as underlying HSC dysfunction in aging.

Keywords:  CD38; aging; hematopoiesis; mitochondria; mitochondrial calcium uniporter; nicotinamide adenine dinucleotide metabolism

DOI:  https://doi.org/10.1097/IN9.0000000000000048
Indian J Pediatr. 2024 Oct 09.

Clinico-Radiological and Genotypic Spectrum of Nuclear Mitochondriopathies.

Neerja Gupta, Bhawana Aggarwal, Anushree Mishra, Madhumita Roy Chowdhury, Sheffali Gulati, Atin Kumar, Madhulika Kabra.

  Mitochondrial disorders are a diverse group of diseases caused by mutations in genes encoded by either nuclear or mitochondrial DNA. In a group of patients with nuclear mitochondriopathies, the authors analysed the clinico-radiological and genotypic spectrum. The study included 25 patients with a genetic diagnosis of nuclear mitochondrial cytopathy who were seen over a 5 y period. There were 25 patients in the study cohort (Mean age of presentation- 14 mo). Biallelic mutations involving nuclear mitochondrial genes were identified in all 25 of them. In 13 and 9 patients, respectively, respiratory chain defects (complex I and complex IV) and mitochondrial DNA depletion syndromes were identified. Twelve novel variants were identified. Interestingly, NDUFV1 with a south Indian founder variant c.1156 C > T (p.Arg386Cys) was the commonest variant. Accurate phenotyping combined with next generation sequencing aids in the precise diagnosis of mitochondrial nuclear gene defects and provides the opportunity for appropriate counseling.

Keywords:   NDUFV1 ; Mitochondriopathies; Nuclear; Respiratory chain defects

DOI:  https://doi.org/10.1007/s12098-024-05266-z
RNA Biol. 2024 Jan;21(1): 28-39

Mitochondrial RNA maturation.

Zofia M Chrzanowska-Lightowlers, Robert N Lightowlers.

  The vast majority of oxygen-utilizing eukaryotes need to express their own mitochondrial genome, mtDNA, to survive. In comparison to size of their nuclear genome, mtDNA is minimal, even in the most exceptional examples. Having evolved from bacteria in an endosymbiotic event, it might be expected that the process of mtDNA expression would be relatively simple. The aim of this short review is to illustrate just how wrong this assumption is. The production of functional mitochondrial RNA across species evolved in many directions. Organelles use a dizzying array of RNA processing, modifying, editing, splicing and maturation events that largely require the import of nuclear-encoded proteins from the cytosol. These processes are sometimes driven by the unusual behaviour of the mitochondrial genome from which the RNA is originally transcribed, but in many examples the complex processes that are essential for the production of functional RNA in the organelle, are fascinating and bewildering.

Keywords:  Mitochondrial; maturation; messenger RNA; modifications; processing; translation

DOI:  https://doi.org/10.1080/15476286.2024.2414157
Brain Nerve. 2024 Oct;76(10): 1127-1135

[Taurine for Mitochondrial Diseases].

Yoshihide Sunada.

Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome is characterized by a mitochondrial DNA mutation that leads to defective taurine modification of the leucine tRNA anticodon, with consequent impaired translation of the UUG codon. This defect reduces synthesis of respiratory chain complexes, which causes energy failure. Taurine supplementation improved mitochondrial function in MELAS model cells. A physician-initiated clinical trial reported that high-dose taurine supplementation therapy suppressed stroke-like episodes and improved taurine modification rates in leukocytes.

DOI: https://doi.org/10.11477/mf.1416202748
Biochem Soc Trans. 2024 Oct 08. pii: BST20221364. [Epub ahead of print]

Coordinating BNIP3/NIX-mediated mitophagy in space and time.

Natalie M Niemi, Jonathan R Friedman.

  Mitochondria maintain organellar homeostasis through multiple quality control pathways, including the clearance of defective or unwanted mitochondria by selective autophagy. This removal of mitochondria, mitophagy, is controlled in large part by the outer mitochondrial membrane mitophagy receptors BNIP3 and NIX. While it has long been appreciated that BNIP3 and NIX mediate mitophagy by controlling the recruitment of autophagic machinery to the mitochondrial surface, the requirement for the carefully controlled spatiotemporal regulation of receptor-mediated mitophagy has only recently come to light. Several new factors that regulate the BNIP3/NIX-mediated mitophagy pathway have emerged, and various loss-of-function cell and animal models have revealed the dire consequences of their dysregulation. In this mini-review, we discuss new insights into the mechanisms and roles of the regulation of BNIP3 and NIX and highlight questions that have emerged from the identification of these new regulators.

Keywords:  autophagy; mitochondria; mitophagy

DOI:  https://doi.org/10.1042/BST20221364
Proc Natl Acad Sci U S A. 2024 Oct 15. 121(42): e2411672121

Nuclear compensatory evolution driven by mito-nuclear incompatibilities.

Debora Princepe, Marcus A M de Aguiar.

  Mitochondrial function relies on the coordinated expression of mitochondrial and nuclear genes, exhibiting remarkable resilience despite high mitochondrial mutation rates. The nuclear compensation mechanism suggests deleterious mitochondrial alleles drive compensatory nuclear mutations to preserve mito-nuclear compatibility. However, prevalence and factors conditioning this phenomenon remain debated due to its conflicting evidence. Here, we investigate how mito-nuclear incompatibilities impact substitutions in a model for species radiation. Mating success depends on genetic compatibility (nuclear DNA) and spatial proximity. Populations evolve from partially compatible mito-nuclear states, simulating mitochondrial DNA (mtDNA) introgression. Mutations do not confer advantages nor disadvantages, but individual fecundity declines with increasing incompatibilities, selecting for mito-nuclear coordination. We find that selection for mito-nuclear compatibility affects each genome differently based on their initial state. In compatible gene pairs, selection reduces substitutions in both genomes, while in incompatible nuclear genes, it consistently promotes compensation, facilitated by more mismatches. Interestingly, high mitochondrial mutation rates can reduce nuclear compensation by increasing mtDNA rectification, while substitutions in initially compatible nuclear gene are boosted. Finally, the presence of incompatibilities accelerates species radiation, but equilibrium richness is not directly correlated to substitution rates, revealing the complex dynamics triggered by mitochondrial introgression and mito-nuclear coevolution. Our study provides a perspective on nuclear compensation and the role of mito-nuclear incompatibilities in speciation by exploring extreme scenarios and identifying trends that empirical data alone cannot reveal. We emphasize the challenges in detecting these dynamics and propose analyzing specific genomic signatures could shed light on this evolutionary process.

Keywords:  mito-nuclear coevolution; mitochondrial mutation rate; mtDNA introgression; nuclear compensation

DOI:  https://doi.org/10.1073/pnas.2411672121
J Transl Genet Genom. 2024 ;8 216-224

Reduced protein kinase C delta in a high molecular weight complex in mitochondria and elevated creatine uptake into Barth syndrome B lymphoblasts.

Edgard M Mejia, Genevieve C Sparagna, Donald W Miller, Grant M Hatch.

  Aim: Barth syndrome (BTHS) is a rare X-linked genetic disease in which mitochondrial oxidative phosphorylation is impaired due to a mutation in the TAFAZZIN gene. The protein kinase C delta (PKCδ) signalosome exists as a high molecular weight complex in mitochondria and controls mitochondrial oxidative phosphorylation.Method: Here, we examined PKCδ levels in mitochondria of aged-matched control and BTHS patient B lymphoblasts and its association with a higher molecular weight complex in mitochondria.
Result: Immunoblot analysis of blue-native polyacrylamide gel electrophoresis mitochondrial fractions revealed an increase in total PKCδ protein expression in BTHS lymphoblasts compared to controls. In contrast, PKCδ associated with a higher molecular weight complex was markedly reduced in BTHS patient B lymphoblasts compared to controls. Given the decrease in PKCδ associated with a higher molecular weight complex in mitochondria, we examined the uptake of creatine, a compound whose utilization is enhanced upon high energy demand. Creatine uptake was markedly elevated in BTHS lymphoblasts compared to controls.
Conclusion: We hypothesize that reduced PKCδ within this higher molecular weight complex in mitochondria may contribute to the bioenergetic defects observed in BTHS lymphoblasts and that enhanced creatine uptake may serve as one of several compensatory mechanisms for the defective mitochondrial oxidative phosphorylation observed in these cells.

Keywords:  B lymphoblasts; Barth syndrome; TAFFAZIN; cardiolipin; creatine uptake; mitochondria; monolysocardiolipin; protein kinase C delta

DOI:  https://doi.org/10.20517/jtgg.2024.11
Redox Biol. 2024 Oct 01. pii: S2213-2317(24)00356-2. [Epub ahead of print]77 103378

Effect of alternative oxidase (AOX) expression on mouse cerebral mitochondria bioenergetics.

Belem Yoval-Sánchez, Ivan Guerrero, Fariha Ansari, Zoya Niatsetskaya, Max Siragusa, Jordi Magrane, Vadim Ten, Csaba Konrad, Marten Szibor, Alexander Galkin.

  Alternative oxidase (AOX) is an enzyme that transfers electrons from reduced quinone directly to oxygen without proton translocation. When AOX from Ciona intestinalis is xenotopically expressed in mice, it can substitute the combined electron-transferring activity of mitochondrial complexes III/IV. Here, we used brain mitochondria from AOX-expressing mice with such a chimeric respiratory chain to study respiratory control bioenergetic mechanisms. AOX expression did not compromise the function of the mammalian respiratory chain at physiological conditions, however the complex IV inhibitor cyanide only partially blocked respiration by AOX-containing mitochondria. The relative fraction of cyanide-insensitive respiration increased at lower temperatures, indicative of a temperature-controlled attenuation of mammalian respiratory enzyme activity. As AOX does not translocate protons, the mitochondrial transmembrane potential in AOX-containing mitochondria was more sensitive to cyanide during succinate oxidation than during malate/pyruvate-supported respiration. High concentrations of cyanide fully collapsed membrane potential during oxidation of either succinate or glycerol 3-phosphate, but not during malate/pyruvate-supported respiration. This confirms AOX's electroneutral redox activity and indicates differences in the proton-translocating capacity of dehydrogenases upstream of the ubiquinone pool. Our respiration data refutes previous proposals for quinone partitioning within the supercomplexes of the respiratory chain, instead supporting the concept of a single homogeneous, freely diffusing quinone pool. Respiration with either succinate or glycerol 3-phosphate promotes reverse electron transfer (RET) towards complex I. AOX expression significantly decreased RET-induced ROS generation, with the effect more pronounced at low temperatures. Inhibitor-sensitivity analysis showed that the AOX-induced decrease in H2O2 release is due to the lower contribution of complex I to net ROS production during RET. Overall, our findings provide new insights into the role of temperature as a mechanism to control respiration and highlight the utility of AOX as a genetic tool to characterize both the distinct pathways of oxygen reduction and the role of redox control in RET.

Keywords:  Alternative quinol oxidase; Complex I; Mitochondria; Mitochondrial membrane potential; ROS generation; Reverse electron transfer

DOI:  https://doi.org/10.1016/j.redox.2024.103378
Proteome Sci. 2024 Oct 08. 22(1): 8

NEK10 kinase ablation affects mitochondrial morphology, function and protein phosphorylation status.

Andressa Peres de Oliveira, Claudia D C Navarro, Pedro Rafael F Dias, Tania Arguello, Brittni R Walker, Sandra R Bacman, Lizandra Maia Sousa, Roger F Castilho, Sílvio R Consonni, Carlos T Moraes, Jörg Kobarg.

BACKGROUND: NEK10, a serine/threonine/tyrosine kinase belonging to the NEK (NIMA-related kinases) family, has been associated with diverse cellular processes. However, no specific target pathways have been identified. Our previous work knocking down NEK10 in HeLa cells suggested a functional association with mitochondria, as we observed altered mitochondrial morphology, mitochondrial oxygen consumption, mtDNA integrity, and reactive oxygen species levels.METHODS: To better understand this association, we studied human HAP1 cells fully knockout for NEK10 and confirmed that NEK10 has an important role in mitochondrial homeostasis. We performed the study of mitochondrial respiration, mitochondrial morphology, mitochondrial mass, and mtDNA analysis. Additionally, we showed proteome and phosphoproteome data of crude mitochondrial fraction of Parental and NEK10 KO cells using liquid chromatography-mass spectrometry (LC-MS/MS).
RESULTS: In the absence of NEK10 several mitochondrial functions were disturbed. Moreover, proteome and phosphoproteome analyses of mitochondrial fractions showed that NEK10 alters the threonine phosphorylation status of several mitochondrial/endoplasmic reticulum components, including HSP60, NDUFB4, and TOM20. These changes impacted the steady-state levels of a larger group of proteins, preferentially involving respiratory complexes and autophagy pathways.
CONCLUSION: We concluded that NEK10 plays a key role in mitochondrial function, possibly by modulating the phosphorylation status of mitochondrial proteins.

DOI: https://doi.org/10.1186/s12953-024-00234-z
Nat Commun. 2024 Oct 08. 15(1): 8723

A germline-to-soma signal triggers an age-related decline of mitochondrial stress response.

Liankui Zhou, Liu Jiang, Lan Li, Chengchuan Ma, Peixue Xia, Wanqiu Ding, Ying Liu.

The abilities of an organism to cope with extrinsic stresses and activate cellular stress responses decline during aging. The signals that modulate stress responses in aged animals remain to be elucidated. Here, we discover that feeding Caenorhabditis elegans (C. elegans) embryo lysates to adult worms enabled the animals to activate the mitochondrial unfolded protein response (UPRmt) upon mitochondrial perturbations. This discovery led to subsequent investigations that unveil a hedgehog-like signal that is transmitted from the germline to the soma in adults to inhibit UPRmt in somatic tissues. Additionally, we find that the levels of germline-expressed piRNAs in adult animals markedly decreased. This reduction in piRNA levels coincides with the production and secretion of a hedgehog-like signal and suppression of the UPRmt in somatic cells. Building upon existing research, our study further elucidates the intricate mechanisms of germline-to-soma signaling and its role in modulating the trade-offs between reproduction and somatic maintenance within the context of organismal aging.

DOI: https://doi.org/10.1038/s41467-024-53064-0
Ageing Res Rev. 2024 Oct 05. pii: S1568-1637(24)00340-4. [Epub ahead of print]101 102522

Mitochondrial Extracellular Vesicles (mitoEVs): Emerging mediators of cell-to-cell communication in health, aging and age-related diseases.

Roberto Iorio, Sabrina Petricca, Giovanna Di Emidio, Stefano Falone, Carla Tatone.

  Mitochondria are metabolic and signalling hubs that integrate a plethora of interconnected processes to maintain cell homeostasis. They are also dormant mediators of inflammation and cell death, and with aging damages affecting mitochondria gradually accumulate, resulting in the manifestation of age-associated disorders. In addition to coordinate multiple intracellular functions, mitochondria mediate intercellular and inter-organ cross talk in different physiological and stress conditions. To fulfil this task, mitochondrial signalling has evolved distinct and complex conventional and unconventional routes of horizontal/vertical mitochondrial transfer. In this regard, great interest has been focused on the ability of extracellular vesicles (EVs), such as exosomes and microvesicles, to carry selected mitochondrial cargoes to target cells, in response to internal and external cues. Over the past years, the field of mitochondrial EVs (mitoEVs) has grown exponentially, revealing unexpected heterogeneity of these structures associated with an ever-expanding mitochondrial function, though the full extent of the underlying mechanisms is far from being elucidated. Therefore, emerging subsets of EVs encompass exophers, migrasomes, mitophers, mitovesicles, and mitolysosomes that can act locally or over long-distances to restore mitochondrial homeostasis and cell functionality, or to amplify disease. This review provides a comprehensive overview of our current understanding of the biology and trafficking of MitoEVs in different physiological and pathological conditions. Additionally, a specific focus on the role of mitoEVs in aging and the onset and progression of different age-related diseases is discussed.

Keywords:  Age-related diseases; Bioenergetic remodelling; Cancer; Intercellular communication; Mitochondria-specific ectocytosis; Mitochondrial derived vesicles (MDVs); Mitochondrial extracellular vesicles (mitoEVs); Mitochondrial quality control (MQC)

DOI:  https://doi.org/10.1016/j.arr.2024.102522
Life Sci Alliance. 2024 Dec;pii: e202403038. [Epub ahead of print]7(12):

Mitochondrial apolipoprotein MIC26 is a metabolic rheostat regulating central cellular fuel pathways.

Melissa Damiecki, Ritam Naha, Yulia Schaumkessel, Philipp Westhoff, Nika Atanelov, Anja Stefanski, Patrick Petzsch, Kai Stühler, Karl Köhrer, Andreas Pm Weber, Ruchika Anand, Andreas S Reichert, Arun Kumar Kondadi.

Mitochondria play central roles in metabolism and metabolic disorders such as type 2 diabetes. MIC26, a mitochondrial contact site and cristae organising system complex subunit, was linked to diabetes and modulation of lipid metabolism. Yet, the functional role of MIC26 in regulating metabolism under hyperglycemia is not understood. We used a multi-omics approach combined with functional assays using WT and MIC26 KO cells cultured in normoglycemia or hyperglycemia, mimicking altered nutrient availability. We show that MIC26 has an inhibitory role in glycolysis and cholesterol/lipid metabolism under normoglycemic conditions. Under hyperglycemia, this inhibitory role is reversed demonstrating that MIC26 is critical for metabolic adaptations. This is partially mediated by alterations of mitochondrial metabolite transporters. Furthermore, MIC26 deletion led to a major metabolic rewiring of glutamine use and oxidative phosphorylation. We propose that MIC26 acts as a metabolic "rheostat," that modulates mitochondrial metabolite exchange via regulating mitochondrial cristae, allowing cells to cope with nutrient overload.

DOI: https://doi.org/10.26508/lsa.202403038
Commun Biol. 2024 Oct 10. 7(1): 1294

ER-mitochondria distance is a critical parameter for efficient mitochondrial Ca2+ uptake and oxidative metabolism.

Giulia Dematteis, Laura Tapella, Claudio Casali, Maria Talmon, Elisa Tonelli, Simone Reano, Adele Ariotti, Emanuela Pessolano, Justyna Malecka, Gabriela Chrostek, Gabrielė Kulkovienė, Danielius Umbrasas, Carla Distasi, Mariagrazia Grilli, Graham Ladds, Nicoletta Filigheddu, Luigia Grazia Fresu, Katsuhiko Mikoshiba, Carlos Matute, Paula Ramos-Gonzalez, Aiste Jekabsone, Tito Calì, Marisa Brini, Marco Biggiogera, Fabio Cavaliere, Riccardo Miggiano, Armando A Genazzani, Dmitry Lim.

IP3 receptor (IP3R)-mediated Ca2+ transfer at the mitochondria-endoplasmic reticulum (ER) contact sites (MERCS) drives mitochondrial Ca2+ uptake and oxidative metabolism and is linked to different pathologies, including Parkinson's disease (PD). The dependence of Ca2+ transfer efficiency on the ER-mitochondria distance remains unexplored. Employing molecular rulers that stabilize ER-mitochondrial distances at 5 nm resolution, and using genetically encoded Ca2+ indicators targeting the ER lumen and the sub-mitochondrial compartments, we now show that a distance of ~20 nm is optimal for Ca2+ transfer and mitochondrial oxidative metabolism due to enrichment of IP3R at MERCS. In human iPSC-derived astrocytes from PD patients, 20 nm MERCS were specifically reduced, which correlated with a reduction of mitochondrial Ca2+ uptake. Stabilization of the ER-mitochondrial interaction at 20 nm, but not at 10 nm, fully rescued mitochondrial Ca2+ uptake in PD astrocytes. Our work determines with precision the optimal distance for Ca2+ flux between ER and mitochondria and suggests a new paradigm for fine control over mitochondrial function.

DOI: https://doi.org/10.1038/s42003-024-06933-9
Cell Biochem Funct. 2024 Sep;42(7): e4131

Targeting Mitochondria: Influence of Metabolites on Mitochondrial Heterogeneity.

Amie N Joof, Fangyuan Ren, Yan Zhou, Mengyu Wang, Jiani Li, Yurong Tan.

  Mitochondria are vital organelles that provide energy for the metabolic processes of cells. These include regulating cellular metabolism, autophagy, apoptosis, calcium ions, and signaling processes. Despite their varying functions, mitochondria are considered semi-independent organelles that possess their own genome, known as mtDNA, which encodes 13 proteins crucial for oxidative phosphorylation. However, their diversity reflects an organism's adaptation to physiological conditions and plays a complex function in cellular metabolism. Mitochondrial heterogeneity exists at the single-cell and tissue levels, impacting cell shape, size, membrane potential, and function. This heterogeneity can contribute to the progression of diseases such as neurodegenerative diseases, metabolic diseases, and cancer. Mitochondrial dynamics enhance the stability of cells and sufficient energy requirement, but these activities are not universal and can lead to uneven mitochondria, resulting in heterogeneity. Factors such as genetics, environmental compounds, and signaling pathways are found to affect these cellular processes and heterogeneity. Additionally, the varying roles of metabolites such as NADH and ATP affect glycolysis's speed and efficiency. An imbalance in metabolites can impair ATP production and redox potential in the mitochondria. Therefore, this review will explore the influence of metabolites in shaping mitochondrial morphology, how these changes contribute to age-related diseases and the therapeutic targets for regulating mitochondrial heterogeneity.

Keywords:  ATP; diseases; fusion/fission; heterogeneity; metabolites; mitochondria; signaling pathway; therapeutic target

DOI:  https://doi.org/10.1002/cbf.4131
Commun Biol. 2024 Oct 05. 7(1): 1267

Metabolic regulation of mitochondrial morphologies in pancreatic beta cells: coupling of bioenergetics and mitochondrial dynamics.

Wen-Wei Tseng, Ching-Hsiang Chu, Yi-Ju Lee, Shirui Zhao, Chen Chang, Yi-Ping Ho, An-Chi Wei.

Cellular bioenergetics and mitochondrial dynamics are crucial for the secretion of insulin by pancreatic beta cells in response to elevated levels of blood glucose. To elucidate the interactions between energy production and mitochondrial fission/fusion dynamics, we combine live-cell mitochondria imaging with biophysical-based modeling and graph-based network analysis. The aim is to determine the mechanism that regulates mitochondrial morphology and balances metabolic demands in pancreatic beta cells. A minimalistic differential equation-based model for beta cells is constructed that includes glycolysis, oxidative phosphorylation, calcium dynamics, and fission/fusion dynamics, with ATP synthase flux and proton leak flux as main regulators of mitochondrial dynamics. The model shows that mitochondrial fission occurs in response to hyperglycemia, starvation, ATP synthase inhibition, uncoupling, and diabetic conditions, in which the rate of proton leakage exceeds the rate of mitochondrial ATP synthesis. Under these metabolic challenges, the propensities of tip-to-tip fusion events simulated from the microscopy images of the mitochondrial networks are lower than those in the control group and prevent the formation of mitochondrial networks. The study provides a quantitative framework that couples bioenergetic regulation with mitochondrial dynamics, offering insights into how mitochondria adapt to metabolic challenges.

DOI: https://doi.org/10.1038/s42003-024-06955-3
Dev Cell. 2024 Oct 07. pii: S1534-5807(24)00532-X. [Epub ahead of print]59(19): 2549-2565

Dynamic death decisions: How mitochondrial dynamics shape cellular commitment to apoptosis and ferroptosis.

Jesminara Khatun, Jesse D Gelles, Jerry Edward Chipuk.

  The incorporation of mitochondria into early eukaryotes established organelle-based biochemistry and enabled metazoan development. Diverse mitochondrial biochemistry is essential for life, and its homeostatic control via mitochondrial dynamics supports organelle quality and function. Mitochondrial crosstalk with numerous regulated cell death (RCD) pathways controls the decision to die. In this review, we will focus on apoptosis and ferroptosis, two distinct forms of RCD that utilize divergent signaling to kill a targeted cell. We will highlight how proteins and processes involved in mitochondrial dynamics maintain biochemically diverse subcellular compartments to support apoptosis and ferroptosis machinery, as well as unite disparate RCD pathways through dual control of organelle biochemistry and the decision to die.

Keywords:  apoptosis; cell biology; cell death; ferroptosis; membranes; mitochondria; mitochondrial dynamics; signal transduction

DOI:  https://doi.org/10.1016/j.devcel.2024.09.004
Biochem Biophys Res Commun. 2024 Oct 05. pii: S0006-291X(24)01273-7. [Epub ahead of print]734 150737

CEAM is a mitochondrial-localized, amyloid-like motif-containing microprotein expressed in human cardiomyocytes.

Ruobing Li, Ti Qin, Yabo Guo, Shan Zhang, Xiaogang Guo.

  Microproteins synthesized through non-canonical translation pathways are frequently found within mitochondria. However, the functional significance of these mitochondria-localized microproteins in energy-intensive organs such as the heart remains largely unexplored. In this study, we demonstrate that the long non-coding RNA CD63-AS1 encodes a mitochondrial microprotein. Notably, in ribosome profiling data of human hearts, there is a positive correlation between the expression of CD63-AS1 and genes associated with cardiomyopathy. We have termed this microprotein CEAM (CD63-AS1 encoded amyloid-like motif containing microprotein), reflecting its sequence characteristics. Our biochemical assays show that CEAM forms protease-resistant aggregates within mitochondria, whereas deletion of the amyloid-like motif transforms CEAM into a soluble cytosolic protein. Overexpression of CEAM triggers mitochondrial stress responses and adversely affect mitochondrial bioenergetics in cultured cardiomyocytes. In turn, the expression of CEAM is reciprocally inhibited by the activation of mitochondrial stresses induced by oligomycin. When expressed in mouse hearts via adeno-associated virus, CEAM impairs cardiac function. However, under conditions of pressure overload-induced cardiac hypertrophy, CEAM expression appears to offer a protective benefit and mitigates the expression of genes associated with cardiac remodeling, presumably through a mechanism that suppresses stress-induced translation reprogramming. Collectively, our study uncovers a hitherto unexplored amyloid-like microprotein expressed in the human cardiomyocytes, offering novel insights into myocardial hypertrophy pathophysiology.

Keywords:  CD63-AS1; Microprotein; Mitochondrial unfolded protein response; Pressure overload-induced cardiac hypertrophy; Transverse aortic constriction

DOI:  https://doi.org/10.1016/j.bbrc.2024.150737
Cell Calcium. 2024 Oct 05. pii: S0143-4160(24)00116-7. [Epub ahead of print]124 102958

The intricacies of mitochondrial calcium and enzyme regulation in liver metabolism.

Cristina Mammucari.

  Mitochondrial Ca2+ plays a positive role in regulating pyruvate dehydrogenase, as well as the TCA cycle enzymes isocitrate dehydrogenase and α-ketoglutarate dehydrogenase. This regulation boosts the production of reducing equivalents that fuel the electron transport chain, ultimately driving ATP production. The Mitochondrial Calcium Uniporter (MCU) is the highly selective channel responsible for mitochondrial Ca2+ uptake when local Ca2+ levels reach the threshold for channel activation. In a recent study, LaMoia et al. used an innovative [13C5]glutamine-based metabolic flux analysis method (Q-flux) to measure in vivo hepatic metabolic fluxes in liver-specific MCU-/- mice. Surprisingly, they observed increased flux through isocitrate dehydrogenase and α-ketoglutarate dehydrogenase. Metabolic pathways are continuously reorganized in response to intrinsic cellular signals, as well as hormonal and nutritional inputs. Integrating metabolic flux analysis into complex systems can provide deeper insights into how metabolic adaptations occur under different conditions.

Keywords:  Calcium; Metabolic flux; Mitochondrial calcium uniporter; TCA cycle

DOI:  https://doi.org/10.1016/j.ceca.2024.102958
bioRxiv. 2024 Sep 24. pii: 2024.09.19.613684. [Epub ahead of print]

Sex-specific decline in prefrontal cortex mitochondrial bioenergetics in aging baboons correlates with walking speed.

Daniel A Adekunbi, Hillary F Huber, Gloria A Benavides, Ran Tian, Cun Li, Peter W Nathanielsz, Jianhua Zhang, Victor Darley-Usmar, Laura A Cox, Adam B Salmon.

Mitochondria play a crucial role in brain aging due to their involvement in bioenergetics, neuroinflammation and brain steroid synthesis. Mitochondrial dysfunction is linked to age-related neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease. We investigated changes in the activities of the electron transport chain (ETC) complexes in normally aging baboon brains and determined how these changes relate to donor sex, morning cortisol levels, and walking speed. Using a novel approach, we assessed mitochondrial bioenergetics from frozen prefrontal cortex (PFC) tissues from a large cohort (60 individuals) of well-characterized aging baboons (6.6-22.8 years, approximately equivalent to 26.4-91.2 human years). Aging was associated with a decline in mitochondrial ETC complexes in the PFC, which was more pronounced when activities were normalized for citrate synthase activity, suggesting that the decline in respiration is predominantly driven by changes in the specific activity of individual complexes rather than changes in mitochondrial number. Moreover, when donor sex was used as a covariate, we found that mitochondrial respiration was preserved with age in females, whereas males showed significant loss of ETC activity with age. Males had higher activities of each individual ETC complex and greater lactate dehydrogenase activity relative to females. Circulating cortisol levels correlated only with complex II-linked respiration in males. We also observed a robust positive predictive relationship between walking speed and respiration linked to complexes I, III, and IV in males but not in females. This data reveals a previously unknown link between aging and bioenergetics across multiple tissues linking frailty and bioenergetic function. This study highlights a potential molecular mechanism for sexual dimorphism in brain resilience and suggests that in males changes in PFC bioenergetics contribute to reduced motor function with age.

DOI: https://doi.org/10.1101/2024.09.19.613684
bioRxiv. 2024 Sep 25. pii: 2024.09.23.614547. [Epub ahead of print]

Inducible and reversible SOD2 knockdown in mouse skeletal muscle drives impaired pyruvate oxidation and reduced metabolic flexibility.

Ethan L Ostrom, Rudy Stuppard, Aurora Mattson-Hughes, David J Marcinek.

Abstract Figure: Highlights: SOD2 knockdown and recovery is achieved in skeletal muscle by using a shRNA targeted to SOD2 mRNA controlled by a tetracycline Response Element and reverse tetracycline transactivator proteinSOD2 KD is induced by administering doxycycline in the drinking waterMitochondrial functional decline and recovery follows the time course of SOD2 protein decline and recoverySustained SOD2 KD precipitates reduced metabolic flexibility in skeletal muscle mitochondria characterized by impaired pyruvate respiration in the presence of other substrates.
Introduction: Skeletal muscle mitochondrial dysfunction is a key characteristic of aging muscle and contributes to age related diseases such as sarcopenia, frailty, and type 2 diabetes. Mitochondrial oxidative distress has been implicated as a driving factor in these age-related diseases, however whether it is a cause, or a consequence of mitochondrial dysfunction remains to be determined. The development of more flexible genetic models is an important tool to test the mechanistic role of mitochondrial oxidative stress on skeletal muscle metabolic dysfunction. We characterize a new model of inducible and reversible mitochondrial redox stress using a tetracycline controlled skeletal muscle specific short hairpin RNA targeted to superoxide dismutase 2 (iSOD2).
Methods: iSOD2 KD and control (CON) animals were administered doxycycline for 3-or 12-weeks and followed for up to 24 weeks and mitochondrial respiration and muscle contraction were measured to define the time course of SOD2 KD and muscle functional changes and recovery.
Results: Maximum knockdown of SOD2 protein occurred by 6 weeks and recovered by 24 weeks after DOX treatment. Mitochondrial aconitase activity and maximum mitochondrial respiration declined in KD muscle by 12 weeks and recovered by 24 weeks. There were minimal changes in gene expression between KD and CON muscle. Twelve-week KD showed a small, but significant decrease in muscle fatigue resistance. The primary phenotype was reduced metabolic flexibility characterized by impaired pyruvate driven respiration when other substrates are present. The pyruvate dehydrogenase kinase inhibitor dichloroacetate partially restored pyruvate driven respiration, while the thiol reductant DTT did not.
Conclusion: We use a model of inducible and reversible skeletal muscle SOD2 knockdown to demonstrate that elevated matrix superoxide reversibly impairs mitochondrial substrate flexibility characterized by impaired pyruvate oxidation. Despite the bioenergetic effect, the limited change in gene expression suggests that the elevated redox stress in this model is confined to the mitochondrial matrix.

DOI: https://doi.org/10.1101/2024.09.23.614547
Sci Adv. 2024 Oct 11. 10(41): eadl4374

Loss of atrial natriuretic peptide signaling causes insulin resistance, mitochondrial dysfunction, and low endurance capacity.

Deborah Carper, Marlène Lac, Marine Coue, Axel Labour, Andre Märtens, Jorge Alberto Ayala Banda, Laurène Mazeyrie, Mie Mechta, Lars Roed Ingerslev, Mohamed Elhadad, Justine Vily Petit, Claire Maslo, Laurent Monbrun, Peggy Del Carmine, Yannis Sainte-Marie, Virginie Bourlier, Claire Laurens, Gilles Mithieux, Denis R Joanisse, Charles Coudray, Christine Feillet-Coudray, Emilie Montastier, Nathalie Viguerie, Geneviève Tavernier, Melanie Waldenberger, Annette Peters, Rui Wang-Sattler, Jerzy Adamski, Karsten Suhre, Christian Gieger, Gabi Kastenmüller, Thomas Illig, Ralf Lichtinghagen, Jochen Seissler, Remy Mounier, Karsten Hiller, Jens Jordan, Romain Barrès, Michaela Kuhn, Dominik Pesta, Cedric Moro.

Type 2 diabetes (T2D) and obesity are strongly associated with low natriuretic peptide (NP) plasma levels and a down-regulation of NP guanylyl cyclase receptor-A (GCA) in skeletal muscle and adipose tissue. However, no study has so far provided evidence for a causal link between atrial NP (ANP)/GCA deficiency and T2D pathogenesis. Here, we show that both systemic and skeletal muscle ANP/GCA deficiencies in mice promote metabolic disturbances and prediabetes. Skeletal muscle insulin resistance is further associated with altered mitochondrial function and impaired endurance running capacity. ANP/GCA-deficient mice exhibit increased proton leak and reduced content of mitochondrial oxidative phosphorylation proteins. We further show that GCA is related to several metabolic traits in T2D and positively correlates with markers of oxidative capacity in human skeletal muscle. Together, these results indicate that ANP/GCA signaling controls muscle mitochondrial integrity and oxidative capacity in vivo and plays a causal role in the development of prediabetes.

DOI: https://doi.org/10.1126/sciadv.adl4374
bioRxiv. 2024 Sep 05. pii: 2024.09.05.611454. [Epub ahead of print]

Mitochondrial topoisomerase I (Top1MT) prevents the onset of metabolic dysfunction-associated steatohepatitis (MASH) in mice.

S A Baechler, L K Saha, V M Factor, C Chitnis, A Dhall, D Becker, J U Marquardt, Y Pommier.

High fat (HF) diet is a major factor in the development of metabolic dysfunction-associated steatotic liver disease (MASLD) and steatohepatis (MASH), and mitochondria have been proposed to play a role in the pathogenesis of HF diet-induced MASH. Because Mitochondrial topoisomerase I (Top1MT) is exclusively present in mitochondria and Top1MT knock-out mice are viable, we were able to assess the role of Top1MT in the development of MASH. We show that after 16 weeks of HF diet, mice lacking Top1MT are prone to the development of severe MASH characterized by liver steatosis, lobular inflammation and hepatocyte damage. Mice lacking Top1MT also show prominent mitochondrial dysfunction, ROS production and mitochondrial DNA (mtDNA) release, accompanied by hepatic inflammation and fibrosis. In summary, our study demonstrates the importance of Top1MT in sustaining hepatocyte functions and suppressing MASH.

DOI: https://doi.org/10.1101/2024.09.05.611454
Biochem Soc Trans. 2024 Oct 11. pii: BST20240319. [Epub ahead of print]

Calcium signaling in mitochondrial intermembrane space.

Shanikumar Goyani, Shatakshi Shukla, Pooja Jadiya, Dhanendra Tomar.

  The mitochondrial intermembrane space (IMS) is a highly protected compartment, second only to the matrix. It is a crucial bridge, coordinating mitochondrial activities with cellular processes such as metabolites, protein, lipid, and ion exchange. This regulation influences signaling pathways for metabolic activities and cellular homeostasis. The IMS harbors various proteins critical for initiating apoptotic cascades and regulating reactive oxygen species production by controlling the respiratory chain. Calcium (Ca2+), a key intracellular secondary messenger, enter the mitochondrial matrix via the IMS, regulating mitochondrial bioenergetics, ATP production, modulating cell death pathways. IMS acts as a regulatory site for Ca2+ entry due to the presence of different Ca2+ sensors such as MICUs, solute carriers (SLCs); ion exchangers (LETM1/SCaMCs); S100A1, mitochondrial glycerol-3-phosphate dehydrogenase, and EFHD1, each with unique Ca2+ binding motifs and spatial localizations. This review primarily emphasizes the role of these IMS-localized Ca2+ sensors concerning their spatial localization, mechanism, and molecular functions. Additionally, we discuss how these sensors contribute to the progression and pathogenesis of various human health conditions and diseases.

Keywords:  Ca2+ sensors; LETM1; MICU; SCaMs; SLC25A12/13; mitochondrial intermembrane space

DOI:  https://doi.org/10.1042/BST20240319
bioRxiv. 2024 Sep 24. pii: 2024.09.20.614121. [Epub ahead of print]

Germline loss diminishes somatic mitochondria but confers preservation of respiratory function during aging and hypothermia.

Hyejin Hwang, Brandon J Berry, Claudette St Croix, Andrew P Wojtovich, Sruti P Shiva, Arjumand Ghazi.

Reproductive status influences metabolism and health across lifespan in diverse ways and mitochondrial function playing a critical role in mediating this relationship. Using the Caenorhabditis elegans germline ablation model, we investigated the impact of germline stem cell (GSC) loss on mitochondrial dynamics and respiratory function. Our results show that GSC loss reduces mitochondrial volume and respiratory function in young adulthood but preserves mitochondrial activity during aging and upon exposure to hypothermic stress, correlating with enhanced survival. We found that the transcription factor NHR-49/PPARα, but not DAF-16/FOXO3A, was essential for preserving mitochondrial function and hypothermia resistance in these long-lived mutants. Together, these findings reveal the impact of germline signals on somatic mitochondrial health and underscore the intricate relationship between reproductive fitness and organismal health.

DOI: https://doi.org/10.1101/2024.09.20.614121
Mol Med. 2024 Oct 10. 30(1): 173

Drp1 acetylation mediated by CDK5-AMPK-GCN5L1 axis promotes cerebral ischemic injury via facilitating mitochondrial fission.

Jiejie Zhang, Shan Wang, Haitao Zhang, Xiaotong Yang, Xin Ren, Lei Wang, Yihan Yang, Yi Yang, Ya Wen.

  The aberrant acetylation of mitochondrial proteins is involved in the pathogenesis of multiple diseases including neurodegenerative diseases and cerebral ischemic injury. Previous studies have shown that depletion of mitochondrial NAD+, which is necessary for mitochondrial deacetylase activity, leads to decreased activity of mitochondrial deacetylase and thus causes hyperacetylation of mitochondrial proteins in ischemic brain tissues, which results in altered mitochondrial dynamics. However, it remains largely unknown about how mitochondrial dynamics-related protein Drp1 is acetylated in ischemic neuronal cells and brain tissues. Here, we showed that Drp1 and GCN5L1 expression was up-regulated in OGD-treated neuronal cells and ischemic brain tissues induced by dMCAO, accompanied by the increased mitochondrial fission, mtROS accumulation, and cell apoptosis. Further, we confirmed that ischemia/hypoxia promoted Drp1 interaction with GCN5L1 in neuronal cells and brain tissues. GCN5L1 knockdown attenuated, while its overexpression enhanced Drp1 acetylation and mitochondrial fission, indicating that GCN5L1 plays a crucial role in ischemia/hypoxia-induced mitochondrial fission by acetylating Drp1. Mechanistically, ischemia/hypoxia induced Drp1 phosphorylation by CDK5 upregulation-mediated activation of AMPK in neuronal cells, which in turn facilitated the interaction of GCN5L1 with Drp1, thus enhancing Drp1 acetylation and mitochondrial fission. Accordingly, inhibition of AMPK alleviated ischemia/hypoxia- induced Drp1 acetylation and mitochondrial fission and protected brain tissues from ischemic damage. These findings provide a novel insight into the functional roles of GCN5L1 in regulating Drp1 acetylation and identify a previously unrecognized CDK5-AMPK-GCN5L1 pathway that mediates the acetylation of Drp1 in ischemic brain tissues.

Keywords:  AMPK; Acetylation; CDK5; Drp1; GCN5L1; Ischemic stroke; Mitochondrial fission; Neuronal cells

DOI:  https://doi.org/10.1186/s10020-024-00948-y
Biol Open. 2024 Jul 15. pii: bio061730. [Epub ahead of print]13(10):

Endonuclease G is dispensable for sperm mitochondrial DNA elimination during spermatogenesis in mice.

Xuefeng Xie, Jianshuang Li, Xue Zhang, Shaomei Mo, Ang Li, Tian-Yi Sun, Feng-Yun Xie, Shi-Ming Luo, Guang Wang, Xiang-Hong Ou, Qing-Yuan Sun, Qinghua Zhou.

  Maternal inheritance of mitochondrial DNA (mtDNA) is a widespread phenomenon in eukaryotes. Our earlier research indicated that sperm mtDNA is removed prior to fertilization in mice, and Endonuclease G (ENDOG) orchestrates the degradation of sperm mitochondria in Caenorhabditis elegans. However, the mechanisms underlying sperm mtDNA disposal in mammals remain poorly understood. To investigate the potential role of ENDOG in sperm mtDNA elimination, we created Endog knockout (Endog-/-) mice. Our findings revealed that Endog-/- mice maintained normal spermatogenesis and fertility. Most strikingly, we detected no substantial discrepancy in sperm mtDNA copy number between Endog-/- and control mice. Furthermore, we noted that sperm mtDNA copy numbers were unchanged in both less motile and motile sperm isolated by Percoll gradient centrifugation from Endog-/- and control mice. Taken together, our results indicate that ENDOG is not essential for spermatogenesis or the elimination of sperm mtDNA in mice.

Keywords:   EndoG ; Maternal inheritance; Mitochondrial DNA; Mitochondrial DNA elimination; Sperm

DOI:  https://doi.org/10.1242/bio.061730
Front Genet. 2024 ;15 1451024

A proteogenomic atlas of the human neural retina.

Tabea V Riepe, Merel Stemerdink, Renee Salz, Alfredo Dueñas Rey, Suzanne E de Bruijn, Erica Boonen, Tomasz Z Tomkiewicz, Michael Kwint, Jolein Gloerich, Hans J C T Wessels, Emma Delanote, Elfride De Baere, Filip van Nieuwerburgh, Sarah De Keulenaer, Barbara Ferrari, Stefano Ferrari, Frauke Coppieters, Frans P M Cremers, Erwin van Wyk, Susanne Roosing, Erik de Vrieze, Peter A C 't Hoen.

  The human neural retina is a complex tissue with abundant alternative splicing and more than 10% of genetic variants linked to inherited retinal diseases (IRDs) alter splicing. Traditional short-read RNA-sequencing methods have been used for understanding retina-specific splicing but have limitations in detailing transcript isoforms. To address this, we generated a proteogenomic atlas that combines PacBio long-read RNA-sequencing data with mass spectrometry and whole genome sequencing data of three healthy human neural retina samples. We identified nearly 60,000 transcript isoforms, of which approximately one-third are novel. Additionally, ten novel peptides confirmed novel transcript isoforms. For instance, we identified a novel IMPDH1 isoform with a novel combination of known exons that is supported by peptide evidence. Our research underscores the potential of in-depth tissue-specific transcriptomic analysis to enhance our grasp of tissue-specific alternative splicing. The data underlying the proteogenomic atlas are available via EGA with identifier EGAD50000000101, via ProteomeXchange with identifier PXD045187, and accessible through the UCSC genome browser.

Keywords:  alternative splicing; inherited retinal disease (IRD); isoform; long-read sequencing; mass spectrometry; multi-omics; neural retina; proteogenomics

DOI:  https://doi.org/10.3389/fgene.2024.1451024
Radiol Case Rep. 2024 Dec;19(12): 6292-6296

Increased ketone levels as a key magnetic resonance spectroscopic findings during acute exacerbation in ECHS1-related Leigh syndrome.

Yuka Murofushi, Kenta Ochiai, Madoka Yasukochi, Kentaro Sano, Keiko Ichimoto, Kei Murayama, Yasushi Okazaki, Taku Omata, Jun-Ichi Takanashi.

  Short-chain enoyl-CoA hydratase, encoded by ECHS1, plays a major role in the valine catabolic pathway and mitochondrial fatty acid β-oxidation. Deficiency of this enzyme causes Leigh syndrome. Herein, we report a case of ECHS1-related Leigh syndrome with a prominent ketone body spectrum on magnetic resonance spectroscopy during acute exacerbation. A 6-month-old boy with mild motor developmental delay presented with disturbances of consciousness and hypercapnia without prior infection or feeding failure. Upon admission, investigations revealed prominent ketosis and elevated 2,3-dihydroxy-2-methylbutyric acid excretion. Brain magnetic resonance imaging revealed symmetrical T2 prolongation with restricted diffusion in the basal ganglia. Magnetic resonance spectroscopy showed a prominent ketone body spectrum in the cerebral white matter, and prominent ketone bodies, elevated lactate and markedly decreased N-acetylaspartate levels in the basal ganglia. Genetic analysis identified compound heterozygous variants of ECHS1. Short-chain enoyl-CoA hydratase deficiency is a disease for which a valine-restricted diet is reported to be beneficial, and early diagnosis is desirable. Severe ketosis and the ketone body magnetic resonance spectroscopy spectrum during acute exacerbation may aid in the diagnosis of this disease.

Keywords:  ECHS1; Ketosis; Leigh syndrome; Magnetic resonance spectroscopy; Metabolic encephalopathies

DOI:  https://doi.org/10.1016/j.radcr.2024.08.164
Nat Biotechnol. 2024 Oct 09.

One-step nanoscale expansion microscopy reveals individual protein shapes.

Ali H Shaib, Abed Alrahman Chouaib, Rajdeep Chowdhury, Jonas Altendorf, Daniel Mihaylov, Chi Zhang, Donatus Krah, Vanessa Imani, Russell K W Spencer, Svilen Veselinov Georgiev, Nikolaos Mougios, Mehar Monga, Sofiia Reshetniak, Tiago Mimoso, Han Chen, Parisa Fatehbasharzad, Dagmar Crzan, Kim-Ann Saal, Mohamad Mahdi Alawieh, Nadia Alawar, Janna Eilts, Jinyoung Kang, Alireza Soleimani, Marcus Müller, Constantin Pape, Luis Alvarez, Claudia Trenkwalder, Brit Mollenhauer, Tiago F Outeiro, Sarah Köster, Julia Preobraschenski, Ute Becherer, Tobias Moser, Edward S Boyden, A Radu Aricescu, Markus Sauer, Felipe Opazo, Silvio O Rizzoli.

The attainable resolution of fluorescence microscopy has reached the subnanometer range, but this technique still fails to image the morphology of single proteins or small molecular complexes. Here, we expand the specimens at least tenfold, label them with conventional fluorophores and image them with conventional light microscopes, acquiring videos in which we analyze fluorescence fluctuations. One-step nanoscale expansion (ONE) microscopy enables the visualization of the shapes of individual membrane and soluble proteins, achieving around 1-nm resolution. We show that conformational changes are readily observable, such as those undergone by the ~17-kDa protein calmodulin upon Ca2+ binding. ONE is also applied to clinical samples, analyzing the morphology of protein aggregates in cerebrospinal fluid from persons with Parkinson disease, potentially aiding disease diagnosis. This technology bridges the gap between high-resolution structural biology techniques and light microscopy, providing new avenues for discoveries in biology and medicine.

DOI: https://doi.org/10.1038/s41587-024-02431-9
Cell Rep. 2024 Oct 10. pii: S2211-1247(24)01190-2. [Epub ahead of print]43(10): 114839

Mitochondrial MOF regulates energy metabolism in heart failure via ATP5B hyperacetylation.

Yuehuai Hu, Yongjia Zheng, Cui Liu, Yuyu You, Ying Wu, Panxia Wang, Yiyang Wu, Hongjun Ba, Jing Lu, Yanqiu Yuan, Peiqing Liu, Yang Mao.

  Lysine acetylation is a conserved post-translational modification involved in energy metabolism in mitochondria and heart function. This study investigates the role of mitochondria-localized lysine acetyltransferase MOF (males absent on the first) in heart failure (HF). We find that MOF is upregulated in mitochondria during HF, and overexpression of mitochondria-targeted MOF (mtMOF) in mouse models results in mitochondria dysfunction, cardiac remodeling, and HF. Furthermore, sirtuin 3 (SIRT3) knockout aggravates mtMOF-induced damages, underscoring the role of MOF-catalyzed hyperacetylation in HF. Quantitative lysine acetylome analysis identifies ATP5B as a substrate of MOF. We demonstrate that the acetylation of ATP5B at K201, co-regulated by MOF and SIRT3, impairs mitochondrial respiration and energy metabolism both in vitro and in vivo. These findings suggest that the role of MOF in HF could be attributed to its regulation of ATP5B acetylation. Overall, our results highlight the disruptive impact of mitochondrial MOF on cardiac function and emphasize the significance of enzyme-catalyzed acetylation in mitochondria.

Keywords:  ATP5B; CP: Metabolism; CP: Molecular biology; KAT8; MOF; SIRT3; acetylation; heart failure; mitochondria

DOI:  https://doi.org/10.1016/j.celrep.2024.114839
Orphanet J Rare Dis. 2024 Oct 11. 19(1): 376

TARS2 c.470 C > G is a chinese-specific founder mutation in three unrelated families with mitochondrial encephalomyopathy.

Shujie Zhang, Haisong Qin, Qingming Wang, Yingfei Wang, Yanhui Liu, Qi Yang, Jingsi Luo, Zailong Qin, Xiang Ji, Lijuan Kan, Guoxing Geng, Jing Huang, Shengkai Wei, Qiuli Chen, Yiping Shen, Haiming Yuan, Baoling Lai.

  Biallelic pathogenic variants in TARS2 lead to combined oxidative phosphorylation deficiency, subtype 21 (COXPD21, MIM #615918), which is a rare mitochondrial encephalomyopathy (ME) characterized by early-onset severe axial hypotonia, limb hypertonia, psychomotor developmental delay, epilepsy and brain anomalies. To date, approximately 28 individuals with COXPD21 and 28 TARS2 variants have been identified. In this study, we reported additional four individuals from three unrelated Chinese families with mitochondrial encephalomyopathy caused by pathogenic variants in TARS2, and described the novel clinical phenotypes and genotypic information. In addition to two novel variants (c.512G > A, p.Arg171Lys; c.988dup, p.Arg330Lysfs*4), one previously reported variant (c.470 C > G, p.Thr157Arg) recurred in six Chinese individuals with COXPD21 but was not present in populations of other races. Our findings expanded the mutation spectrum of TARS2 and confirmed that c.470 C > G is a Chinese-specific founder mutation. The novel phenotypes, including reduced fetal movement, eye anomalies and sleep irregularities, observed in our patients enriched the clinical characteristics of COXPD21.

Keywords:   TARS2 ; COXPD21; Chinese-specific; Founder mutation; Mitochondrial encephalomyopathy

DOI:  https://doi.org/10.1186/s13023-024-03365-w
Front Cell Dev Biol. 2024 ;12 1466915

Imaging and proteomics toolkits for studying organelle contact sites.

Rico Gamuyao, Chi-Lun Chang.

  Organelle contact sites are regions where two heterologous membranes are juxtaposed by molecular tethering complexes. These contact sites are important in inter-organelle communication and cellular functional integration. However, visualizing these minute foci and identifying contact site proteomes have been challenging. In recent years, fluorescence-based methods have been developed to visualize the dynamic physical interaction of organelles while proximity labeling approaches facilitate the profiling of proteomes at contact sites. In this review, we explain the design principle for these contact site reporters: a dual-organelle interaction mechanism based on how endogenous tethers and/or tethering complexes localize to contact sites. We classify the contact site reporters into three categories: (i) single-protein systems, (ii) two-component systems with activated reporter signal upon organelle proximity, and (iii) reporters for contact site proteomes. We also highlight advanced imaging analysis with high temporal-spatial resolution and the use of machine-learning algorithms for detecting contact sites.

Keywords:  bimolecular complementation; electron microscopy; light microscopy; organelle contact sites; proximity labeling; split fluorescent protein; split-TurboID; splitFAST

DOI:  https://doi.org/10.3389/fcell.2024.1466915
Proc Natl Acad Sci U S A. 2024 Oct 15. 121(42): e2403450121

Natural variation in age-related dopamine neuron degeneration is glutathione dependent and linked to life span.

Colin R Coleman, Judit Pallos, Alicia Arreola-Bustos, Lu Wang, Daniel Raftery, Daniel E L Promislow, Ian Martin.

  Aging is the biggest risk factor for Parkinson's disease (PD), suggesting that age-related changes in the brain promote dopamine neuron vulnerability. It is unclear, however, whether aging alone is sufficient to cause significant dopamine neuron loss, and if so, how this intersects with PD-related neurodegeneration. Here, through examining a large collection of naturally varying Drosophila strains, we find a strong relationship between life span and age-related dopamine neuron loss. Strains with naturally short-lived animals exhibit a loss of dopamine neurons without generalized neurodegeneration, while animals from long-lived strains retain dopamine neurons across age. Metabolomic profiling reveals lower glutathione levels in short-lived strains which is associated with elevated levels of reactive oxygen species (ROS), sensitivity to oxidative stress, and vulnerability to silencing the familial PD gene parkin. Strikingly, boosting neuronal glutathione levels via glutamate-cysteine ligase (Gcl) overexpression is sufficient to normalize ROS levels, extend life span, and block dopamine neurons loss in short-lived backgrounds, demonstrating that glutathione deficiencies are central to neurodegenerative phenotypes associated with short longevity. These findings may be relevant to human PD pathogenesis, where glutathione depletion is reported to occur in the idiopathic PD patient brain through unknown mechanisms. Building on this, we find reduced expression of the Gcl catalytic subunit in both Drosophila strains vulnerable to age-related dopamine neuron loss and in the human brain from familial PD patients harboring the common LRRK2 G2019S mutation. Our study across Drosophila and human PD systems suggests that glutathione synthesis and levels play a conserved role in regulating age-related dopamine neuron health.

Keywords:  Parkinson’s disease; aging; glutathione; neurodegeneration

DOI:  https://doi.org/10.1073/pnas.2403450121
Front Pharmacol. 2024 ;15 1358646

FGF21 inhibits ferroptosis caused by mitochondrial damage to promote the repair of peripheral nerve injury.

Yao Yan, Xinyu Ran, Zihan Zhou, Yuting Gu, Rendu Wang, Chuanqi Qiu, Yinuo Sun, Jifeng Wang, Jian Xiao, Yingfeng Lu, Jian Wang.

  Introduction: Ferroptosis is a new type of cell death characterized by lipid peroxidation and iron dependency, representing an emerging disease regulation mechanism. The limited understanding of ferroptosis in peripheral nerve injury (PNI) complicates the management of such injuries. Mitochondrial dysfunction, which contributes to ferroptosis, further exacerbates the challenges of peripheral nerve repair.Methods: In this study, we established an in vitro model of Schwann cells model treated with TBHP and an in vivo sciatic nerve crush injury model in rats. These models were used to investigate the effects of fibroblast growth factor 21 (FGF21) on PNI, both in vitro and in vivo, and to explore the potential mechanisms linking injury-induced ferroptosis and mitochondrial dysfunction.
Results: Our findings reveal that PNI triggers abnormal accumulation of lipid reactive oxygen species (ROS) and inactivates mitochondrial respiratory chain complex III, leading to mitochondrial dysfunction. This dysfunction catalyzes the oxidation of excessive polyunsaturated fatty acids, resulting in antioxidant imbalance and loss of ferroptosis suppressor protein 1 (FSP1), which drives lipid peroxidation. Additionally, irregular iron metabolism, defective mitophagy, and other factors contribute to the induction of ferroptosis. Importantly, we found that FGF21 attenuates the abnormal accumulation of lipid ROS, restores mitochondrial function, and suppresses ferroptosis, thus promoting PNI repair. Notably, glutathione peroxidase 4 (GPX4), a downstream target of nuclear factor E2-related factor 2 (Nrf2), and the ERK/Nrf2 pathway are involved in the regulation of ferroptosis by FGF21.
Conclusion: FGF21 promotes peripheral nerve repair by inhibiting ferroptosis caused by mitochondrial dysfunction. Therefore, targeting mitochondria and ferroptosis represents a promising therapeutic strategy for effective PNI repair.

Keywords:  ROS; ferroptosis; fibroblast growth factor 21 (FGF21); lipid peroxidation; mitochondria; peripheral nerve injury; schwann cell

DOI:  https://doi.org/10.3389/fphar.2024.1358646