bims-mitmed 2023-03-12 papers

bims-mitmed

Biomed News

on Mitochondrial medicine

Issue of 2023‒03‒12
33 papers selected by
Dario Brunetti
Fondazione IRCCS Istituto Neurologico

Fumarate induces vesicular release of mtDNA to drive innate immunity.
Modeling mitochondrial DNA diseases: from base editing to pluripotent stem-cell-derived organoids.
A mitochondrial SCF-FBXL4 ubiquitin E3 ligase complex degrades BNIP3 and NIX to restrain mitophagy and prevent mitochondrial disease.
Recessive pathogenic variants in MCAT cause combined oxidative phosphorylation deficiency.
Mitochondrial molecule controls inflammation.
Determinants and outcomes of mitochondrial dynamics.
The Role of Mitophagy in Skeletal Muscle Damage and Regeneration.
Parkinson's Disease, Parkinsonisms, and Mitochondria: the Role of Nuclear and Mitochondrial DNA.
FDA approves first Friedreich's ataxia drug.
The autophagy-NAD axis in longevity and disease.
Mitochondria Localized microRNAs: An Unexplored miRNA Niche in Alzheimer's Disease and Aging.
Germline TFAM levels regulate mitochondrial DNA copy number and mutant heteroplasmy in C. elegans.
MT-ATP6 mitochondrial disease identified by newborn screening reveals a distinct biochemical phenotype.
Proliferating Astrocytes in Primary Culture Do Not Depend upon Mitochondrial Respiratory Complex I Activity or Oxidative Phosphorylation.
Leber Hereditary Optic Neuropathy in a Family of Carriers of MT-ND5 m.13042G>T (A236S) Novel Variant.
Disease-associated oligodendrocyte signatures are spatiotemporally dysregulated in spinocerebellar ataxia type 3.
Fractal dynamics of individual mitochondrial oscillators measure local inter-mitochondrial coupling.
Optic Nerve Injury Enhanced Mitochondrial Fission and Increased Mitochondrial Density without Altering the Uniform Mitochondrial Distribution in the Unmyelinated Axons of Retinal Ganglion Cells in a Mouse Model.
Pathophysiology and Management of Fatigue in Neuromuscular Diseases.
Real-Time Visualization of Cytosolic and Mitochondrial ATP Dynamics in Response to Metabolic Stress in Cultured Cells.
Transferred mitochondria accumulate reactive oxygen species, promoting proliferation.
Optogenetic rejuvenation of mitochondrial membrane potential extends C. elegans lifespan.
Monitoring Live Mitochondrial Metabolism in Real-Time Using NMR Spectroscopy.
Mitochondrial redox adaptations enable alternative aspartate synthesis in SDH-deficient cells.
Protocol to differentiate monolayer human induced pluripotent stem cells into inflammatory responsive astrocytes.
Nicotinamide riboside rescues dysregulated glycolysis and fatty acid β-oxidation in a human hepatic cell model of Citrin deficiency.
MiR-146a in ALS: Contribution to Early Peripheral Nerve Degeneration and Relevance as Disease Biomarker.
Preservation of mitochondrial membrane potential is necessary for lifespan extension from dietary restriction.
MitoStores: a place for precursors to ride out the storm.
Macrophage fumarate hydratase restrains mtRNA-mediated interferon production.
Pioglitazone restores mitochondrial function but does not spare cortical tissue following mild brain contusion.
Maternal and Intrauterine Influences on Feto-Placental Growth Are Accompanied by Sexually Dimorphic Changes in Placental Mitochondrial Respiration, and Metabolic Signalling Pathways.
Mitochondrial dysfunction in hearing loss: Oxidative stress, autophagy and NLRP3 inflammasome.

Nature. 2023 Mar 08.

Fumarate induces vesicular release of mtDNA to drive innate immunity.

Vincent Zecchini, Vincent Paupe, Irene Herranz-Montoya, Joëlle Janssen, Inge M N Wortel, Jordan L Morris, Ashley Ferguson, Suvagata Roy Chowdury, Marc Segarra-Mondejar, Ana S H Costa, Gonçalo C Pereira, Laura Tronci, Timothy Young, Efterpi Nikitopoulou, Ming Yang, Dóra Bihary, Federico Caicci, Shun Nagashima, Alyson Speed, Kalliopi Bokea, Zara Baig, Shamith Samarajiwa, Maxine Tran, Thomas Mitchell, Mark Johnson, Julien Prudent, Christian Frezza.

Mutations in fumarate hydratase (FH) cause hereditary leiomyomatosis and renal cell carcinoma1. Loss of FH in the kidney elicits several oncogenic signalling cascades through the accumulation of the oncometabolite fumarate2. However, although the long-term consequences of FH loss have been described, the acute response has not so far been investigated. Here we generated an inducible mouse model to study the chronology of FH loss in the kidney. We show that loss of FH leads to early alterations of mitochondrial morphology and the release of mitochondrial DNA (mtDNA) into the cytosol, where it triggers the activation of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING)-TANK-binding kinase 1 (TBK1) pathway and stimulates an inflammatory response that is also partially dependent on retinoic-acid-inducible gene I (RIG-I). Mechanistically, we show that this phenotype is mediated by fumarate and occurs selectively through mitochondrial-derived vesicles in a manner that depends on sorting nexin 9 (SNX9). These results reveal that increased levels of intracellular fumarate induce a remodelling of the mitochondrial network and the generation of mitochondrial-derived vesicles, which allows the release of mtDNAin the cytosol and subsequent activation of the innate immune response.

DOI: https://doi.org/10.1038/s41586-023-05770-w
EMBO Rep. 2023 Mar 06. e55678

Modeling mitochondrial DNA diseases: from base editing to pluripotent stem-cell-derived organoids.

Isabella Tolle, Valeria Tiranti, Alessandro Prigione.

  Mitochondrial DNA (mtDNA) diseases are multi-systemic disorders caused by mutations affecting a fraction or the entirety of mtDNA copies. Currently, there are no approved therapies for the majority of mtDNA diseases. Challenges associated with engineering mtDNA have in fact hindered the study of mtDNA defects. Despite these difficulties, it has been possible to develop valuable cellular and animal models of mtDNA diseases. Here, we describe recent advances in base editing of mtDNA and the generation of three-dimensional organoids from patient-derived human-induced pluripotent stem cells (iPSCs). Together with already available modeling tools, the combination of these novel technologies could allow determining the impact of specific mtDNA mutations in distinct human cell types and might help uncover how mtDNA mutation load segregates during tissue organization. iPSC-derived organoids could also represent a platform for the identification of treatment strategies and for probing the in vitro effectiveness of mtDNA gene therapies. These studies have the potential to increase our mechanistic understanding of mtDNA diseases and may open the way to highly needed and personalized therapeutic interventions.

Keywords:  iPSCs; mitochondria; mitochondrial diseases; mitochondrial genome editing; organoids

DOI:  https://doi.org/10.15252/embr.202255678
EMBO J. 2023 Mar 10. e113033

A mitochondrial SCF-FBXL4 ubiquitin E3 ligase complex degrades BNIP3 and NIX to restrain mitophagy and prevent mitochondrial disease.

Yu Cao, Jing Zheng, Huayun Wan, Yuqiu Sun, Song Fu, Shanshan Liu, Baiyu He, Gaihong Cai, Yang Cao, Huanwei Huang, Qi Li, Yan Ma, She Chen, Fengchao Wang, Hui Jiang.

  Mitophagy is a fundamental quality control mechanism of mitochondria. Its regulatory mechanisms and pathological implications remain poorly understood. Here, via a mitochondria-targeted genetic screen, we found that knockout (KO) of FBXL4, a mitochondrial disease gene, hyperactivates mitophagy at basal conditions. Subsequent counter screen revealed that FBXL4-KO hyperactivates mitophagy via two mitophagy receptors BNIP3 and NIX. We determined that FBXL4 functions as an integral outer-membrane protein that forms an SCF-FBXL4 ubiquitin E3 ligase complex. SCF-FBXL4 ubiquitinates BNIP3 and NIX to target them for degradation. Pathogenic FBXL4 mutations disrupt SCF-FBXL4 assembly and impair substrate degradation. Fbxl4-/- mice exhibit elevated BNIP3 and NIX proteins, hyperactive mitophagy, and perinatal lethality. Importantly, knockout of either Bnip3 or Nix rescues metabolic derangements and viability of the Fbxl4-/- mice. Together, beyond identifying SCF-FBXL4 as a novel mitochondrial ubiquitin E3 ligase restraining basal mitophagy, our results reveal hyperactivated mitophagy as a cause of mitochondrial disease and suggest therapeutic strategies.

Keywords:  BNIP3/NIX; FBXL4; mitochondrial disease; mitophagy; ubiquitin-proteasome pathway

DOI:  https://doi.org/10.15252/embj.2022113033
Elife. 2023 Mar 07. pii: e68047. [Epub ahead of print]12

Recessive pathogenic variants in MCAT cause combined oxidative phosphorylation deficiency.

Bryn D Webb, Sara M Nowinski, Ashley Solmonson, Jaya Ganesh, Richard J Rodenburg, Joao Leandro, Anthony Evans, Hieu S Vu, Thomas P Naidich, Bruce D Gelb, Ralph J DeBerardinis, Jared Rutter, Sander M Houten.

  Malonyl-CoA-acyl carrier protein transacylase (MCAT) is an enzyme involved in mitochondrial fatty acid synthesis (mtFAS) and catalyzes the transfer of the malonyl moiety of malonyl-CoA to the mitochondrial acyl carrier protein (ACP). Previously, we showed that loss-of-function of mtFAS genes, including Mcat, is associated with severe loss of electron transport chain (ETC) complexes in mouse immortalized skeletal myoblasts (Nowinski et al., 2020). Here, we report a proband presenting with hypotonia, failure to thrive, nystagmus, and abnormal brain MRI findings. Using whole exome sequencing, we identified biallelic variants in MCAT. Protein levels for NDUFB8 and COXII, subunits of complex I and IV respectively, were markedly reduced in lymphoblasts and fibroblasts, as well as SDHB for complex II in fibroblasts. ETC enzyme activities were decreased in parallel. Re-expression of wild-type MCAT rescued the phenotype in patient fibroblasts. This is the first report of a patient with MCAT pathogenic variants and combined oxidative phosphorylation deficiency.

Keywords:  MCAT; genetics; genomics; human; mitochondria; mitochondrial disease

DOI:  https://doi.org/10.7554/eLife.68047
Nature. 2023 Mar 08.

Mitochondrial molecule controls inflammation.

Taylor A Poor, Navdeep S Chandel.



Keywords:  Cell biology; Immunology; Metabolism

DOI:  https://doi.org/10.1038/d41586-023-00596-y
Mol Cell. 2023 Feb 28. pii: S1097-2765(23)00115-6. [Epub ahead of print]

Determinants and outcomes of mitochondrial dynamics.

Rubén Quintana-Cabrera, Luca Scorrano.

  Mitochondria are not only central organelles in metabolism and energy conversion but are also platforms for cellular signaling cascades. Classically, the shape and ultrastructure of mitochondria were depicted as static. The discovery of morphological transitions during cell death and of conserved genes controlling mitochondrial fusion and fission contributed to establishing the concept that mitochondrial morphology and ultrastructure are dynamically regulated by mitochondria-shaping proteins. These finely tuned, dynamic changes in mitochondrial shape can in turn control mitochondrial function, and their alterations in human diseases suggest that this space can be explored for drug discovery. Here, we review the basic tenets and molecular mechanisms of mitochondrial morphology and ultrastructure, describing how they can coordinately define mitochondrial function.

Keywords:  cristae; cristae remodeling; fusion fission; mitochondria

DOI:  https://doi.org/10.1016/j.molcel.2023.02.012
Cells. 2023 Feb 24. pii: 716. [Epub ahead of print]12(5):

The Role of Mitophagy in Skeletal Muscle Damage and Regeneration.

Eirini Chatzinikita, Maria Maridaki, Konstantinos Palikaras, Michael Koutsilieris, Anastassios Philippou.

  Mitochondria are cellular organelles that play an essential role in generating the chemical energy needed for the biochemical reactions in cells. Mitochondrial biogenesis, i.e., de novo mitochondria formation, results in enhanced cellular respiration, metabolic processes, and ATP generation, while autophagic clearance of mitochondria (mitophagy) is required to remove damaged or useless mitochondria. The balance between the opposing processes of mitochondrial biogenesis and mitophagy is highly regulated and crucial for the maintenance of the number and function of mitochondria as well as for the cellular homeostasis and adaptations to metabolic demands and extracellular stimuli. In skeletal muscle, mitochondria are essential for maintaining energy homeostasis, and the mitochondrial network exhibits complex behaviors and undergoes dynamic remodeling in response to various conditions and pathologies characterized by changes in muscle cell structure and metabolism, such as exercise, muscle damage, and myopathies. In particular, the involvement of mitochondrial remodeling in mediating skeletal muscle regeneration following damage has received increased attention, as modifications in mitophagy-related signals arise from exercise, while variations in mitochondrial restructuring pathways can lead to partial regeneration and impaired muscle function. Muscle regeneration (through myogenesis) following exercise-induced damage is characterized by a highly regulated, rapid turnover of poor-functioning mitochondria, permitting the synthesis of better-functioning mitochondria to occur. Nevertheless, essential aspects of mitochondrial remodeling during muscle regeneration remain poorly understood and warrant further characterization. In this review, we focus on the critical role of mitophagy for proper muscle cell regeneration following damage, highlighting the molecular mechanisms of the mitophagy-associated mitochondrial dynamics and network reformation.

Keywords:  exercise; mitochondrial biogenesis; mitochondrial network; mitophagy; muscle damage; myogenesis; regeneration

DOI:  https://doi.org/10.3390/cells12050716
Curr Neurol Neurosci Rep. 2023 Mar 07.

Parkinson's Disease, Parkinsonisms, and Mitochondria: the Role of Nuclear and Mitochondrial DNA.

A Legati, D Ghezzi.

  PURPOSE OF REVIEW: Overwhelming evidence indicates that mitochondrial dysfunction is a central factor in Parkinson's disease (PD) pathophysiology. This paper aims to review the latest literature published, focusing on genetic defects and expression alterations affecting mitochondria-associated genes, in support of their key role in PD pathogenesis.RECENT FINDINGS: Thanks to the use of new omics approaches, a growing number of studies are discovering alterations affecting genes with mitochondrial functions in patients with PD and parkinsonisms. These genetic alterations include pathogenic single-nucleotide variants, polymorphisms acting as risk factors, and transcriptome modifications, affecting both nuclear and mitochondrial genes. We will focus on alterations of mitochondria-associated genes described by studies conducted on patients or on animal/cellular models of PD or parkinsonisms. We will comment how these findings can be taken into consideration for improving the diagnostic procedures or for deepening our knowledge on the role of mitochondrial dysfunctions in PD.

Keywords:  Mitochondria; Mitochondrial DNA; Nuclear DNA; Omics; Parkinsonism; Parkinson’s disease

DOI:  https://doi.org/10.1007/s11910-023-01260-8
Nat Rev Drug Discov. 2023 Mar 08.

FDA approves first Friedreich's ataxia drug.

Asher Mullard.

DOI: https://doi.org/10.1038/d41573-023-00041-9
Trends Cell Biol. 2023 Mar 04. pii: S0962-8924(23)00023-5. [Epub ahead of print]

The autophagy-NAD axis in longevity and disease.

Niall Wilson, Tetsushi Kataura, Miriam E Korsgen, Congxin Sun, Sovan Sarkar, Viktor I Korolchuk.

  Autophagy is an intracellular degradation pathway that recycles subcellular components to maintain metabolic homeostasis. NAD is an essential metabolite that participates in energy metabolism and serves as a substrate for a series of NAD+-consuming enzymes (NADases), including PARPs and SIRTs. Declining levels of autophagic activity and NAD represent features of cellular ageing, and consequently enhancing either significantly extends health/lifespan in animals and normalises metabolic activity in cells. Mechanistically, it has been shown that NADases can directly regulate autophagy and mitochondrial quality control. Conversely, autophagy has been shown to preserve NAD levels by modulating cellular stress. In this review we highlight the mechanisms underlying this bidirectional relationship between NAD and autophagy, and the potential therapeutic targets it provides for combatting age-related disease and promoting longevity.

Keywords:  PARP; Parkinson's disease; ageing; mitophagy; neurodegeneration; nicotinamide; sirtuins

DOI:  https://doi.org/10.1016/j.tcb.2023.02.004
Cells. 2023 Feb 25. pii: 742. [Epub ahead of print]12(5):

Mitochondria Localized microRNAs: An Unexplored miRNA Niche in Alzheimer's Disease and Aging.

Jazmin Rivera, Laxman Gangwani, Subodh Kumar.

  Mitochondria play several vital roles in the brain cells, especially in neurons to provide synaptic energy (ATP), Ca2+ homeostasis, Reactive Oxygen Species (ROS) production, apoptosis, mitophagy, axonal transport and neurotransmission. Mitochondrial dysfunction is a well-established phenomenon in the pathophysiology of many neurological diseases, including Alzheimer's disease (AD). Amyloid-beta (Aβ) and Phosphorylated tau (p-tau) proteins cause the severe mitochondrial defects in AD. A newly discovered cellular niche of microRNAs (miRNAs), so-called mitochondrial-miRNAs (mito-miRs), has recently been explored in mitochondrial functions, cellular processes and in a few human diseases. The mitochondria localized miRNAs regulate local mitochondrial genes expression and are significantly involved in the modulation of mitochondrial proteins, and thereby in controlling mitochondrial function. Thus, mitochondrial miRNAs are crucial to maintaining mitochondrial integrity and for normal mitochondrial homeostasis. Mitochondrial dysfunction is well established in AD pathogenesis, but unfortunately mitochondria miRNAs and their precise roles have not yet been investigated in AD. Therefore, an urgent need exists to examine and decipher the critical roles of mitochondrial miRNAs in AD and in the aging process. The current perspective sheds light on the latest insights and future research directions on investigating the contribution of mitochondrial miRNAs in AD and aging.

Keywords:  Alzheimer’s disease; aging; mitochondrial dysfunction; mitochondrial miRNAs; synaptic energy

DOI:  https://doi.org/10.3390/cells12050742
MicroPubl Biol. 2023 ;2023

Germline TFAM levels regulate mitochondrial DNA copy number and mutant heteroplasmy in C. elegans.

Aaron Z A Schwartz, Jeremy Nance.

The mitochondrial genome (mtDNA) is packaged into discrete protein-DNA complexes called nucleoids. mtDNA packaging factor TFAM (mitochondrial transcription factor-A) promotes nucleoid compaction and is required for mtDNA replication. Here, we investigate how changing TFAM levels affects mtDNA in the Caenorhabditis elegans germ line. We show that increasing germline TFAM activity boosts mtDNA number and significantly increases the relative proportion of a selfish mtDNA mutant, uaDf5 . We conclude that TFAM levels must be tightly controlled to ensure appropriate mtDNA composition in the germ line.

DOI: https://doi.org/10.17912/micropub.biology.000727
Am J Med Genet A. 2023 Mar 08.

MT-ATP6 mitochondrial disease identified by newborn screening reveals a distinct biochemical phenotype.

Christina G Tise, Courtney P Verscaj, Bryce A Mendelsohn, Jeremy Woods, Chung U Lee, Gregory M Enns, Zinandré Stander, Patricia L Hall, Tina M Cowan, Kristina P Cusmano-Ozog.

  Although decreased citrulline is used as a newborn screening (NBS) marker to identify proximal urea cycle disorders (UCDs), it is also a feature of some mitochondrial diseases, including MT-ATP6 mitochondrial disease. Here we describe biochemical and clinical features of 11 children born to eight mothers from seven separate families who were identified with low citrulline by NBS (range 3-5 μM; screening cutoff >5) and ultimately diagnosed with MT-ATP6 mitochondrial disease. Follow-up testing revealed a pattern of hypocitrullinemia together with elevated propionyl-(C3) and 3-hydroxyisovaleryl-(C5-OH) acylcarnitines, and a homoplasmic pathogenic variant in MT-ATP6 in all cases. Single and multivariate analysis of NBS data from the 11 cases using Collaborative Laboratory Integrated Reports (CLIR; https://clir.mayo.edu) demonstrated citrulline <1st percentile, C3 > 50th percentile, and C5-OH >90th percentile when compared with reference data, as well as unequivocal separation from proximal UCD cases and false-positive low citrulline cases using dual scatter plots. Five of the eight mothers were symptomatic at the time of their child(ren)'s diagnosis, and all mothers and maternal grandmothers evaluated molecularly and biochemically had a homoplasmic pathogenic variant in MT-ATP6, low citrulline, elevated C3, and/or elevated C5-OH. All molecularly confirmed individuals (n = 17) with either no symptoms (n = 12), migraines (n = 1), or a neurogenic muscle weakness, ataxia, and retinitis pigmentosa (NARP) phenotype (n = 3) were found to have an A or U mitochondrial haplogroup, while one child with infantile-lethal Leigh syndrome had a B haplogroup.

Keywords:  MT-ATP6 mitochondrial disease; elevated C3; elevated C5-OH; low citrulline; newborn screening; proximal urea cycle disorders

DOI:  https://doi.org/10.1002/ajmg.a.63159
Cells. 2023 Feb 21. pii: 683. [Epub ahead of print]12(5):

Proliferating Astrocytes in Primary Culture Do Not Depend upon Mitochondrial Respiratory Complex I Activity or Oxidative Phosphorylation.

Ellen A Silva, Ana P Dalla Costa, Juliana S Ruas, Edilene S Siqueira-Santos, Annelise Francisco, Roger F Castilho.

  Understanding the role of astrocytes in the development of the nervous system and neurodegenerative disorders implies a necessary knowledge of the oxidative metabolism of proliferating astrocytes. The electron flux through mitochondrial respiratory complexes and oxidative phosphorylation may impact the growth and viability of these astrocytes. Here, we aimed at assessing to which extent mitochondrial oxidative metabolism is required for astrocyte survival and proliferation. Primary astrocytes from the neonatal mouse cortex were cultured in a physiologically relevant medium with the addition of piericidin A or oligomycin at concentrations that fully inhibit complex I-linked respiration and ATP synthase, respectively. The presence of these mitochondrial inhibitors for up to 6 days in a culture medium elicited only minor effects on astrocyte growth. Moreover, neither the morphology nor the proportion of glial fibrillary acidic protein-positive astrocytes in culture was affected by piericidin A or oligomycin. Metabolic characterization of the astrocytes showed a relevant glycolytic metabolism under basal conditions, despite functional oxidative phosphorylation and large spare respiratory capacity. Our data suggest that astrocytes in primary culture can sustainably proliferate when their energy metabolism relies only on aerobic glycolysis since their growth and survival do not require electron flux through respiratory complex I or oxidative phosphorylation.

Keywords:  OXPHOS; astrocytes; bioenergetic; mitochondria; oligomycin; piericidin A

DOI:  https://doi.org/10.3390/cells12050683
J Neuroophthalmol. 2023 Mar 10.

Leber Hereditary Optic Neuropathy in a Family of Carriers of MT-ND5 m.13042G>T (A236S) Novel Variant.

Sanja Petrović Pajić, Maja Suštar Habjan, Jelka Brecelj, Ana Fakin, Marija Volk, Aleš Maver, Gregor Jezernik, Borut Peterlin, Damjan Glavač, Marko Hawlina, Martina Jarc-Vidmar.

BACKGROUND: A Slovenian three-generation family with 3 individuals with bilateral optic neuropathy and 2 unaffected relatives with a novel homoplasmic missense variant m.13042G > T (A236S) in the ND5 gene is described. A detailed phenotype at initial diagnosis and a follow-up of bilateral optic neuropathy progression is presented for 2 affected individuals.METHODS: A detailed phenotype analysis with clinical examination in the early and chronic phase with electrophysiology and OCT segmentation is presented. Genotype analysis with full mitochondrial genome sequencing was performed.
RESULTS: Two affected male individuals (maternal cousins) had a profound visual loss at an early age (11 and 20 years) with no recovery. The maternal grandmother exhibited bilateral optic atrophy with a history of visual loss at the age 58 years. The visual loss of both affected male individuals was characterized by centrocecal scotoma, abnormal color vision, abnormal PERG N95, and VEP. Later with disease progression, retinal nerve fiber layer thinning was observed on OCT. We observed no other extraocular clinical features. Mitochondrial sequencing identified a homoplasmic novel variant m.13042G > T (A236S) in the MT-ND5 gene, belonging to a haplogroup K1a.
CONCLUSION: Novel homoplasmic variant m.13042G > T (A236S) in the ND5 gene in our family was associated with Leber hereditary optic neuropathy-like phenotype. However, predicting the pathogenicity of a novel ultra-rare missense variant in the mitochondrial ND5 gene is challenging. Genetic counseling should consider genotypic and phenotypic heterogeneity, incomplete penetrance, haplogroup type, and tissue-specific thresholds.

DOI: https://doi.org/10.1097/WNO.0000000000001820
Front Neurosci. 2023 ;17 1118429

Disease-associated oligodendrocyte signatures are spatiotemporally dysregulated in spinocerebellar ataxia type 3.

Kristen H Schuster, Danielle M DiFranco, Alexandra F Putka, Juan P Mato, Sabrina I Jarrah, Nicholas R Stec, Vikram O Sundararajan, Hayley S McLoughlin.

  Spinocerebellar ataxia type 3 (SCA3) is a neurodegenerative disease caused by a CAG repeat expansion in the ATXN3 gene. Though the ATXN3 protein is expressed ubiquitously throughout the CNS, regional pathology in SCA3 patients is observed within select neuronal populations and more recently within oligodendrocyte-rich white matter tracts. We have previously recapitulated these white matter abnormalities in an overexpression mouse model of SCA3 and demonstrated that oligodendrocyte maturation impairments are one of the earliest and most progressive changes in SCA3 pathogenesis. Disease-associated oligodendrocyte signatures have recently emerged as significant contributors to several other neurodegenerative diseases, including Alzheimer's disease, Huntington's disease, and Parkinson's disease, but their role in regional vulnerability and disease progression remains unexplored. Here, we are the first to comparatively assess myelination in human tissue in a region-dependent manner. Translating these findings to SCA3 mouse models of disease, we confirmed endogenous expression of mutant Atxn3 leads to regional transcriptional dysregulation of oligodendrocyte maturation markers in Knock-In models of SCA3. We then investigated the spatiotemporal progression of mature oligodendrocyte transcriptional dysregulation in an overexpression SCA3 mouse model and how it relates to the onset of motor impairment. We further determined that regional reduction in mature oligodendrocyte cell counts in SCA3 mice over time parallels the onset and progression of brain atrophy in SCA3 patients. This work emphasizes the prospective contributions of disease-associated oligodendrocyte signatures to regional vulnerability and could inform timepoints and target regions imperative for biomarker assessment and therapeutic intervention in several neurodegenerative diseases.

Keywords:  MJD; Machado-Joseph disease; SCA3; myelination; polyglutamine (polyQ) diseases

DOI:  https://doi.org/10.3389/fnins.2023.1118429
Biophys J. 2023 Mar 09. pii: S0006-3495(23)00164-9. [Epub ahead of print]

Fractal dynamics of individual mitochondrial oscillators measure local inter-mitochondrial coupling.

Felix T Kurz, Miguel A Aon, Heinz-Peter Schlemmer, Johann Me Jende, Brian O'Rourke, Antonis A Armoundas.

  Mitochondrial inner membrane potentials in cardiomyocytes may oscillate in cycles of depolarization/repolarization when the mitochondrial network is exposed to metabolic or oxidative stress. The frequencies of such oscillations are dynamically changing while clusters of weakly coupled mitochondrial oscillators adjust to a common phase and frequency. Across the cardiac myocyte, the averaged signal of the mitochondrial population follows self-similar or fractal dynamics; however, fractal properties of individual mitochondrial oscillators have not yet been examined. We show that the largest synchronously oscillating cluster exhibits a fractal dimension,D, that is indicative of self-similar behavior with D=1.27±0.11, in contrast to the remaining network mitochondria whose fractal dimension is close to that of Brownian noise,D=1.58±0.10 . We further demonstrate that fractal behavior is correlated with local coupling mechanisms, while it is only weakly linked to measures of functional connections between mitochondria. Our findings suggest that individual mitochondrial fractal dimensions may serve as a simple measure of local mitochondrial coupling.

Keywords:  cardiac myocyte; fractal dimension; mitochondrial oscillator; wavelets

DOI:  https://doi.org/10.1016/j.bpj.2023.03.011
Int J Mol Sci. 2023 Feb 22. pii: 4356. [Epub ahead of print]24(5):

Optic Nerve Injury Enhanced Mitochondrial Fission and Increased Mitochondrial Density without Altering the Uniform Mitochondrial Distribution in the Unmyelinated Axons of Retinal Ganglion Cells in a Mouse Model.

Takahiro Tsuji, Tomoya Murase, Yoshiyuki Konishi, Masaru Inatani.

  Glaucomatous optic neuropathy (GON), a major cause of blindness, is characterized by the loss of retinal ganglion cells (RGCs) and the degeneration of their axons. Mitochondria are deeply involved in maintaining the health of RGCs and their axons. Therefore, lots of attempts have been made to develop diagnostic tools and therapies targeting mitochondria. Recently, we reported that mitochondria are uniformly distributed in the unmyelinated axons of RGCs, possibly owing to the ATP gradient. Thus, using transgenic mice expressing yellow fluorescent protein targeting mitochondria exclusively in RGCs within the retina, we assessed the alteration of mitochondrial distributions induced by optic nerve crush (ONC) via in vitro flat-mount retinal sections and in vivo fundus images captured with a confocal scanning ophthalmoscope. We observed that the mitochondrial distribution in the unmyelinated axons of survived RGCs after ONC remained uniform, although their density increased. Furthermore, via in vitro analysis, we discovered that the mitochondrial size is attenuated following ONC. These results suggest that ONC induces mitochondrial fission without disrupting the uniform mitochondrial distribution, possibly preventing axonal degeneration and apoptosis. The in vivo visualization system of axonal mitochondria in RGCs may be applicable in the detection of the progression of GON in animal studies and potentially in humans.

Keywords:  Thy1-mito-YFP mice; confocal scanning ophthalmoscope; distribution; glaucoma; mitochondria; optic nerve crush; optic neuropathy

DOI:  https://doi.org/10.3390/ijms24054356
Int J Mol Sci. 2023 Mar 05. pii: 5005. [Epub ahead of print]24(5):

Pathophysiology and Management of Fatigue in Neuromuscular Diseases.

Francesca Torri, Piervito Lopriore, Vincenzo Montano, Gabriele Siciliano, Michelangelo Mancuso, Giulia Ricci.

  Fatigue is a major determinant of quality of life and motor function in patients affected by several neuromuscular diseases, each of them characterized by a peculiar physiopathology and the involvement of numerous interplaying factors. This narrative review aims to provide an overview on the pathophysiology of fatigue at a biochemical and molecular level with regard to muscular dystrophies, metabolic myopathies, and primary mitochondrial disorders with a focus on mitochondrial myopathies and spinal muscular atrophy, which, although fulfilling the definition of rare diseases, as a group represent a representative ensemble of neuromuscular disorders that the neurologist may encounter in clinical practice. The current use of clinical and instrumental tools for fatigue assessment, and their significance, is discussed. A summary of therapeutic approaches to address fatigue, encompassing pharmacological treatment and physical exercise, is also overviewed.

Keywords:  fatigue; metabolic myopathies; mitochondrial diseases; muscular dystrophies; neuromuscular disorders; spinal muscular atrophy

DOI:  https://doi.org/10.3390/ijms24055005
Cells. 2023 Feb 22. pii: 695. [Epub ahead of print]12(5):

Real-Time Visualization of Cytosolic and Mitochondrial ATP Dynamics in Response to Metabolic Stress in Cultured Cells.

Donnell White, Lothar Lauterboeck, Parnia Mobasheran, Tetsuya Kitaguchi, Antoine H Chaanine, Qinglin Yang.

  Adenosine 5' triphosphate (ATP) is the energy currency of life, which is produced in mitochondria (~90%) and cytosol (less than 10%). Real-time effects of metabolic changes on cellular ATP dynamics remain indeterminate. Here we report the design and validation of a genetically encoded fluorescent ATP indicator that allows for real-time, simultaneous visualization of cytosolic and mitochondrial ATP in cultured cells. This dual-ATP indicator, called smacATPi (simultaneous mitochondrial and cytosolic ATP indicator), combines previously described individual cytosolic and mitochondrial ATP indicators. The use of smacATPi can help answer biological questions regarding ATP contents and dynamics in living cells. As expected, 2-deoxyglucose (2-DG, a glycolytic inhibitor) led to substantially decreased cytosolic ATP, and oligomycin (a complex V inhibitor) markedly decreased mitochondrial ATP in cultured HEK293T cells transfected with smacATPi. With the use of smacATPi, we can also observe that 2-DG treatment modestly attenuates mitochondrial ATP and oligomycin reduces cytosolic ATP, indicating the subsequent changes of compartmental ATP. To evaluate the role of ATP/ADP carrier (AAC) in ATP trafficking, we treated HEK293T cells with an AAC inhibitor, Atractyloside (ATR). ATR treatment attenuated cytosolic and mitochondrial ATP in normoxia, suggesting AAC inhibition reduces ADP import from the cytosol to mitochondria and ATP export from mitochondria to cytosol. In HEK293T cells subjected to hypoxia, ATR treatment increased mitochondrial ATP along with decreased cytosolic ATP, implicating that ACC inhibition during hypoxia sustains mitochondrial ATP but may not inhibit the reversed ATP import from the cytosol. Furthermore, both mitochondrial and cytosolic signals decrease when ATR is given in conjunction with 2-DG in hypoxia. Thus, real-time visualization of spatiotemporal ATP dynamics using smacATPi provides novel insights into how cytosolic and mitochondrial ATP signals respond to metabolic changes, providing a better understanding of cellular metabolism in health and disease.

Keywords:  ATP; biosensor; fluorescence; metabolism; mitochondria

DOI:  https://doi.org/10.3390/cells12050695
Elife. 2023 Mar 06. pii: e85494. [Epub ahead of print]12

Transferred mitochondria accumulate reactive oxygen species, promoting proliferation.

Chelsea U Kidwell, Joseph R Casalini, Soorya Pradeep, Sandra D Scherer, Daniel Greiner, Defne Bayik, Dionysios C Watson, Gregory S Olson, Justin D Lathia, Jarrod S Johnson, Jared Rutter, Alana L Welm, Thomas A Zangle, Minna Roh-Johnson.

  Recent studies reveal that lateral mitochondrial transfer, the movement of mitochondria from one cell to another, can affect cellular and tissue homeostasis1,2. Most of what we know about mitochondrial transfer stems from bulk cell studies and have led to the paradigm that functional transferred mitochondria restore bioenergetics and revitalize cellular functions to recipient cells with damaged or non-functional mitochondrial networks3. However, we show that mitochondrial transfer also occurs between cells with functioning endogenous mitochondrial networks, but the mechanisms underlying how transferred mitochondria can promote such sustained behavioral reprogramming remain unclear. We report that unexpectedly, transferred macrophage mitochondria are dysfunctional and accumulate reactive oxygen species in recipient cancer cells. We further discovered that reactive oxygen species accumulation activates ERK signaling, promoting cancer cell proliferation. Pro-tumorigenic macrophages exhibit fragmented mitochondrial networks, leading to higher rates of mitochondrial transfer to cancer cells. Finally, we observe that macrophage mitochondrial transfer promotes tumor cell proliferation in vivo. Collectively these results indicate that transferred macrophage mitochondria activate downstream signaling pathways in a ROS-dependent manner in cancer cells, and provide a model of how sustained behavioral reprogramming can be mediated by a relatively small amount of transferred mitochondria in vitro and in vivo.

Keywords:  cancer biology; cell biology; human; mouse

DOI:  https://doi.org/10.7554/eLife.85494
Nat Aging. 2023 Feb;3(2): 157-161

Optogenetic rejuvenation of mitochondrial membrane potential extends C. elegans lifespan.

Brandon J Berry, Anežka Vodičková, Annika Müller-Eigner, Chen Meng, Christina Ludwig, Matt Kaeberlein, Shahaf Peleg, Andrew P Wojtovich.

Mitochondrial dysfunction plays a central role in aging but the exact biological causes are still being determined. Here, we show that optogenetically increasing mitochondrial membrane potential during adulthood using a light-activated proton pump improves age-associated phenotypes and extends lifespan in C. elegans. Our findings provide direct causal evidence that rescuing the age-related decline in mitochondrial membrane potential is sufficient to slow the rate of aging and extend healthspan and lifespan.

DOI: https://doi.org/10.1038/s43587-022-00340-7
Magn Reson Chem. 2023 Mar 07.

Monitoring Live Mitochondrial Metabolism in Real-Time Using NMR Spectroscopy.

G A Nagana Gowda, Vadim Pascua, John A Lusk, Natalie N Hong, Lin Guo, Jiang Dong, Ian R Sweet, Daniel Raftery.

  Investigation of mitochondrial metabolism is gaining increased interest owing to the growing recognition of the role of mitochondria in health and numerous diseases. Studies of isolated mitochondria promise novel insights into the metabolism devoid of confounding effects from other cellular organelles such as cytoplasm. This study describes the isolation of mitochondria from mouse skeletal myoblast cells (C2C12) and the investigation of live mitochondrial metabolism in real time using isotope tracer-based NMR spectroscopy. [3-13 C1 ]pyruvate was used as the substrate to monitor the dynamic changes of the downstream metabolites in mitochondria. The results demonstrate an intriguing phenomenon, in which lactate is produced from pyruvate inside the mitochondria and the results were confirmed by treating mitochondria with an inhibitor of mitochondrial pyruvate carrier (UK5099). Lactate is associated with health and numerous diseases including cancer and, to date, it is known to occur only in the cytoplasm. The insight that lactate is also produced inside mitochondria opens avenues for exploring new pathways of lactate metabolism. Further, experiments performed using inhibitors of the mitochondrial respiratory chain, FCCP and rotenone, show that [2-13 C1 ]acetyl coenzyme A, which is produced from [3-13 C1 ]pyruvate and acts as a primary substrate for the tricarboxylic acid cycle in mitochondria, exhibits a remarkable sensitivity to the inhibitors. These results offer a direct approach to visualize mitochondrial respiration through altered levels of the associated metabolites.

Keywords:  13C; 1H; NMR; [2-13C1]acetyl coenzyme A; [3-13C1]lactate; [3-13C1]pyruvate; live mitochondria; metabolism

DOI:  https://doi.org/10.1002/mrc.5341
Elife. 2023 Mar 08. pii: e78654. [Epub ahead of print]12

Mitochondrial redox adaptations enable alternative aspartate synthesis in SDH-deficient cells.

Madeleine L Hart, Evan Quon, Anna-Lena B G Vigil, Ian A Engstrom, Oliver J Newsom, Kristian Davidsen, Pia Hoellerbauer, Samantha M Carlisle, Lucas B Sullivan.

  The oxidative tricarboxylic acid (TCA) cycle is a central mitochondrial pathway integrating catabolic conversions of NAD+ to NADH and anabolic production of aspartate, a key amino acid for cell proliferation. Several TCA cycle components are implicated in tumorigenesis, including loss of function mutations in subunits of succinate dehydrogenase (SDH), also known as complex II of the electron transport chain (ETC), but mechanistic understanding of how proliferating cells tolerate the metabolic defects of SDH loss is still lacking. Here, we identify that SDH supports human cell proliferation through aspartate synthesis but, unlike other ETC impairments, the effects of SDH inhibition are not ameliorated by electron acceptor supplementation. Interestingly, we find aspartate production and cell proliferation are restored to SDH-impaired cells by concomitant inhibition of ETC complex I (CI). We determine that the benefits of CI inhibition in this context depend on decreasing mitochondrial NAD+/NADH, which drives SDH-independent aspartate production through pyruvate carboxylation and reductive carboxylation of glutamine. We also find that genetic loss or restoration of SDH selects for cells with concordant CI activity, establishing distinct modalities of mitochondrial metabolism for maintaining aspartate synthesis. These data therefore identify a metabolically beneficial mechanism for CI loss in proliferating cells and reveal how compartmentalized redox changes can impact cellular fitness.

Keywords:  biochemistry; cancer biology; chemical biology; human

DOI:  https://doi.org/10.7554/eLife.78654
STAR Protoc. 2023 Mar 06. pii: S2666-1667(23)00100-4. [Epub ahead of print]4(1): 102142

Protocol to differentiate monolayer human induced pluripotent stem cells into inflammatory responsive astrocytes.

Anna Maria Sole Giordano, Monah Abou Alezz, Ivan Merelli, Anna Kajaste-Rudnitski.

  Glia, and in particular astrocytes, are one of the major players in neurological and neuroinflammatory disorders. Here, we present a protocol to efficiently generate inflammatory responsive astrocytes from human induced pluripotent stem cells in a monolayer culture. We describe steps for neural differentiation to reach a homogeneous population of neural progenitor cells, followed by their differentiation into neural/glial progenitors. Finally, we detail enrichment to a 90% pure inflammatory responsive astrocyte population. For complete details on the use and execution of this protocol, please refer to Giordano et al.1.

Keywords:  Cell Biology; Cell Differentiation; Immunology; Molecular Biology; Neuroscience; Stem Cells

DOI:  https://doi.org/10.1016/j.xpro.2023.102142
Hum Mol Genet. 2023 Mar 06. pii: ddad018. [Epub ahead of print]

Nicotinamide riboside rescues dysregulated glycolysis and fatty acid β-oxidation in a human hepatic cell model of Citrin deficiency.

Winifred W Yau, Gao Bin Chen, Jin Zhou, Joel Celio Francisco, Nivetha Kanakaram Thimmukonda, Shang Li, Brijesh Kumar Singh, Paul Michael Yen.

Citrin Deficiency (CD) is an inborn error of metabolism caused by loss-of-function of the mitochondrial aspartate/glutamate transporter, CITRIN, which is involved in both the urea cycle and malate aspartate shuttle. Patients with CD develop hepatosteatosis and hyperammonemia but there is no effective therapy for CD. Currently, there are no animal models that faithfully recapitulate the human CD phenotype. Accordingly, we generated a CITRIN knockout HepG2 cell line using CRISPR/Cas 9 genome editing technology to study metabolic and cell signaling defects in CD. CITRIN KO cells showed increased ammonia accumulation, higher cytosolic NADH/NAD+ ratio and reduced glycolysis. Surprisingly, these cells showed impaired fatty acid metabolism and mitochondrial activity. CITRIN KO cells also displayed increased cholesterol and bile acid metabolism resembling those observed in CD patients. Remarkably, normalizing cytosolic NADH:NAD+ ratio by nicotinamide riboside (NR) increased glycolysis and fatty acid oxidation but had no effect on the hyperammonemia suggesting the urea cycle defect was independent of the aspartate/malate shuttle defect of CD. The correction of glycolysis and fatty acid metabolism defects in CITRIN KO cells by reducing cytoplasmic NADH:NAD+ levels suggests this may be a novel strategy to treat some of the metabolic defects of CD and other mitochondrial diseases.

DOI: https://doi.org/10.1093/hmg/ddad018
Int J Mol Sci. 2023 Feb 27. pii: 4610. [Epub ahead of print]24(5):

MiR-146a in ALS: Contribution to Early Peripheral Nerve Degeneration and Relevance as Disease Biomarker.

Eleonora Giagnorio, Claudia Malacarne, Paola Cavalcante, Letizia Scandiffio, Marco Cattaneo, Viviana Pensato, Cinzia Gellera, Nilo Riva, Angelo Quattrini, Eleonora Dalla Bella, Giuseppe Lauria, Renato Mantegazza, Silvia Bonanno, Stefania Marcuzzo.

  Amyotrophic lateral sclerosis (ALS) is characterized by the progressive, irreversible loss of upper and lower motor neurons (UMNs, LMNs). MN axonal dysfunctions are emerging as relevant pathogenic events since the early ALS stages. However, the exact molecular mechanisms leading to MN axon degeneration in ALS still need to be clarified. MicroRNA (miRNA) dysregulation plays a critical role in the pathogenesis of neuromuscular diseases. These molecules represent promising biomarkers for these conditions since their expression in body fluids consistently reflects distinct pathophysiological states. Mir-146a has been reported to modulate the expression of the NFL gene, encoding the light chain of the neurofilament (NFL) protein, a recognized biomarker for ALS. Here, we analyzed miR-146a and Nfl expression in the sciatic nerve of G93A-SOD1 ALS mice during disease progression. The miRNA was also analyzed in the serum of affected mice and human patients, the last stratified relying on the predominant UMN or LMN clinical signs. We revealed a significant miR-146a increase and Nfl expression decrease in G93A-SOD1 peripheral nerve. In the serum of both ALS mice and human patients, the miRNA levels were reduced, discriminating UMN-predominant patients from the LMN ones. Our findings suggest a miR-146a contribution to peripheral axon impairment and its potential role as a diagnostic and prognostic biomarker for ALS.

Keywords:  amyotrophic lateral sclerosis; axon degeneration; biomarker; microRNA-146a

DOI:  https://doi.org/10.3390/ijms24054610
Geroscience. 2023 Mar 06.

Preservation of mitochondrial membrane potential is necessary for lifespan extension from dietary restriction.

Brandon J Berry, Evan Mjelde, Fatima Carreno, Kathryn Gilham, Emily J Hanson, Emily Na, Matt Kaeberlein.

  Dietary restriction (DR) increases lifespan in many organisms, but its underlying mechanisms are not fully understood. Mitochondria play a central role in metabolic regulation and are known to undergo changes in structure and function in response to DR. Mitochondrial membrane potential (Δψm) is the driving force for ATP production and mitochondrial outputs that integrate many cellular signals. One such signal regulated by Δψm is nutrient-status sensing. Here, we tested the hypothesis that DR promotes longevity through preserved Δψm during adulthood. Using the nematode Caenorhabditis elegans, we find that Δψm declines with age relatively early in the lifespan, and this decline is attenuated by DR. Pharmacologic depletion of Δψm blocked the longevity and health benefits of DR. Genetic perturbation of Δψm and mitochondrial ATP availability similarly prevented lifespan extension from DR. Taken together, this study provides further evidence that appropriate regulation of Δψm is a critical factor for health and longevity in response to DR.

Keywords:  Aging; Bioenergetics; Calorie restriction; Fasting; Metabolism; Mitochondrial uncoupling

DOI:  https://doi.org/10.1007/s11357-023-00766-w
EMBO J. 2023 Mar 06. e113576

MitoStores: a place for precursors to ride out the storm.

Megan Balzarini, Zixuan Yuan, Hilla Weidberg.

The fate of unimported mitochondrial precursors has been increasingly studied in recent years, mostly focusing on protein degradation. In this issue of the EMBO journal, Krämer et al discovered MitoStores, a new protective mechanism that temporarily stores mitochondrial proteins in cytosolic deposits.

DOI: https://doi.org/10.15252/embj.2023113576
Nature. 2023 Mar 08.

Macrophage fumarate hydratase restrains mtRNA-mediated interferon production.

Alexander Hooftman, Christian G Peace, Dylan G Ryan, Emily A Day, Ming Yang, Anne F McGettrick, Maureen Yin, Erica N Montano, Lihong Huo, Juliana E Toller-Kawahisa, Vincent Zecchini, Tristram A J Ryan, Alfonso Bolado-Carrancio, Alva M Casey, Hiran A Prag, Ana S H Costa, Gabriela De Los Santos, Mariko Ishimori, Daniel J Wallace, Swamy Venuturupalli, Efterpi Nikitopoulou, Norma Frizzell, Cecilia Johansson, Alexander Von Kriegsheim, Michael P Murphy, Caroline Jefferies, Christian Frezza, Luke A J O'Neill.

Metabolic rewiring underlies the effector functions of macrophages1-3, but the mechanisms involved remain incompletely defined. Here, using unbiased metabolomics and stable isotope-assisted tracing, we show that an inflammatory aspartate-argininosuccinate shunt is induced following lipopolysaccharide stimulation. The shunt, supported by increased argininosuccinate synthase (ASS1) expression, also leads to increased cytosolic fumarate levels and fumarate-mediated protein succination. Pharmacological inhibition and genetic ablation of the tricarboxylic acid cycle enzyme fumarate hydratase (FH) further increases intracellular fumarate levels. Mitochondrial respiration is also suppressed and mitochondrial membrane potential increased. RNA sequencing and proteomics analyses demonstrate that there are strong inflammatory effects resulting from FH inhibition. Notably, acute FH inhibition suppresses interleukin-10 expression, which leads to increased tumour necrosis factor secretion, an effect recapitulated by fumarate esters. Moreover, FH inhibition, but not fumarate esters, increases interferon-β production through mechanisms that are driven by mitochondrial RNA (mtRNA) release and activation of the RNA sensors TLR7, RIG-I and MDA5. This effect is recapitulated endogenously when FH is suppressed following prolonged lipopolysaccharide stimulation. Furthermore, cells from patients with systemic lupus erythematosus also exhibit FH suppression, which indicates a potential pathogenic role for this process in human disease. We therefore identify a protective role for FH in maintaining appropriate macrophage cytokine and interferon responses.

DOI: https://doi.org/10.1038/s41586-023-05720-6
Brain Commun. 2023 ;5(2): fcad032

Pioglitazone restores mitochondrial function but does not spare cortical tissue following mild brain contusion.

W Brad Hubbard, Hemendra J Vekaria, Olivia J Kalimon, Malinda L Spry, Emily P Brown, Todd J Kilbaugh, Patrick G Sullivan.

  Pioglitazone interacts through the mitochondrial protein mitoNEET to improve brain bioenergetics following traumatic brain injury. To provide broader evidence regarding the therapeutic effects of pioglitazone after traumatic brain injury, the current study is focused on immediate and delayed therapy in a model of mild brain contusion. To assess pioglitazone therapy on mitochondrial bioenergetics in cortex and hippocampus, we use a technique to isolate subpopulations of total, glia-enriched and synaptic mitochondria. Pioglitazone treatment was initially administered at either 0.25, 3, 12 or 24 h following mild controlled cortical impact. At 48 h post-injury, ipsilateral cortex and hippocampus were dissected and mitochondrial fractions were isolated. Maximal mitochondrial respiration injury-induced deficits were observed in total and synaptic fractions, and 0.25 h pioglitazone treatment following mild controlled cortical impact was able to restore respiration to sham levels. While there are no injury-induced deficits in hippocampal fractions, we do find that 3 h pioglitazone treatment after mild controlled cortical impact can significantly increase maximal mitochondrial bioenergetics compared to vehicle-treated mild controlled cortical impact group. However, delayed pioglitazone treatment initiated at either 3 or 24 h after mild brain contusion does not improve spared cortical tissue. We demonstrate that synaptic mitochondrial deficits following mild focal brain contusion can be restored with early initiation of pioglitazone treatment. Further investigation is needed to determine functional improvements with pioglitazone beyond that of overt cortical tissue sparing following mild contusion traumatic brain injury.

Keywords:  TBI; bioenergetics; mitoNEET; oxidative stress; traumatic brain injury

DOI:  https://doi.org/10.1093/braincomms/fcad032
Cells. 2023 Mar 03. pii: 797. [Epub ahead of print]12(5):

Maternal and Intrauterine Influences on Feto-Placental Growth Are Accompanied by Sexually Dimorphic Changes in Placental Mitochondrial Respiration, and Metabolic Signalling Pathways.

Esteban Salazar-Petres, Daniela Pereira-Carvalho, Jorge Lopez-Tello, Amanda N Sferruzzi-Perri.

  Adverse maternal environments such as small size, malnutrition, and metabolic conditions are known to influence fetal growth outcomes. Similarly, fetal growth and metabolic alterations may alter the intrauterine environment and affect all fetuses in multiple gestation/litter-bearing species. The placenta is the site of convergence between signals derived from the mother and the developing fetus/es. Its functions are fuelled by energy generated by mitochondrial oxidative phosphorylation (OXPHOS). The aim of this study was to delineate the role of an altered maternal and/or fetal/intrauterine environment in feto-placental growth and placental mitochondrial energetic capacity. To address this, in mice, we used disruptions of the gene encoding phosphoinositol 3-kinase (PI3K) p110α, a growth and metabolic regulator to perturb the maternal and/or fetal/intrauterine environment and study the impact on wildtype conceptuses. We found that feto-placental growth was modified by a perturbed maternal and intrauterine environment, and effects were most evident for wildtype males compared to females. However, placental mitochondrial complex I+II OXPHOS and total electron transport system (ETS) capacity were similarly reduced for both fetal sexes, yet reserve capacity was additionally decreased in males in response to the maternal and intrauterine perturbations. These were also sex-dependent differences in the placental abundance of mitochondrial-related proteins (e.g., citrate synthase and ETS complexes), and activity of growth/metabolic signalling pathways (AKT and MAPK) with maternal and intrauterine alterations. Our findings thus identify that the mother and the intrauterine environment provided by littermates modulate feto-placental growth, placental bioenergetics, and metabolic signalling in a manner dependent on fetal sex. This may have relevance for understanding the pathways leading to reduced fetal growth, particularly in the context of suboptimal maternal environments and multiple gestation/litter-bearing species.

Keywords:  PI3K; fetus; mitochondria; placenta; sex

DOI:  https://doi.org/10.3390/cells12050797
Front Cell Dev Biol. 2023 ;11 1119773

Mitochondrial dysfunction in hearing loss: Oxidative stress, autophagy and NLRP3 inflammasome.

Peipei Li, Shen Li, Le Wang, Hongmin Li, Yang Wang, Hongbing Liu, Xin Wang, Xiaodan Zhu, Zhangsuo Liu, Fanglei Ye, Yuan Zhang.

  Sensorineural deafness becomes an inevitable worldwide healthy problem, yet the current curative therapy is limited. Emerging evidences demonstrate mitochondrial dysfunction plays a vital role of in the pathogenesis of deafness. Reactive oxygen species (ROS)-induced mitochondrial dysfunction combined with NLRP3 inflammasome activation is involved in cochlear damage. Autophagy not only clears up undesired proteins and damaged mitochondria (mitophagy), but also eliminate excessive ROS. Appropriate enhancement of autophagy can reduce oxidative stress, inhibit cell apoptosis, and protect auditory cells. In addition, we further discuss the interplays linking ROS generation, NLRP3 inflammasome activation, and autophagy underlying the pathogenesis of deafness, including ototoxic drugs-, noise- and aging-related hearing loss.

Keywords:  NLRP3 inflammasome; autophagy; hearing loss; mitochondrial dysfunction; oxidative stress

DOI:  https://doi.org/10.3389/fcell.2023.1119773