bims-mitmed 2023-07-30 papers

bims-mitmed

Biomed News

on Mitochondrial medicine

Issue of 2023–07–30
23 papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico

Mitochondrial defects leading to arrested spermatogenesis and ferroptosis in the PARL deficient mouse model of Leigh Syndrome.
Complex II Biology in Aging, Health, and Disease.
Hyper-ubiquitylation of DNA helicase RECQL4 by E3 ligase MITOL prevents mitochondrial entry and potentiates mitophagy.
Gene Editing Technologies Targeting TFAM and Its Relation to Mitochondrial Diseases.
UBQLN2 and HSP70 participate in Parkin-mediated mitophagy by facilitating outer mitochondrial membrane rupture.
Mitochondrial proteostasis mediated by CRL5 Ozz and Alix maintains skeletal muscle function.
A method to assess the mitochondrial respiratory capacity of complexes I and II from frozen tissue using the Oroboros O2k-FluoRespirometer.
Nascent mitochondrial proteins initiate the localized condensation of cytosolic protein aggregates on the mitochondrial surface.
Coenzyme Q 4 is a functional substitute for coenzyme Q 10 and can be targeted to the mitochondria.
A Novel ENU-Induced Mfn2 Mutation Causes Motor Deficits in Mice without Causing Peripheral Neuropathy.
Single Cell Transcriptomic Analysis in a Mouse Model of Barth Syndrome Reveals Cell-Specific Alterations in Gene Expression and Intercellular Communication.
A ubiquitin-based effector-to-inhibitor switch coordinates early brain, craniofacial, and skin development.
Mechanism of PGC-1α-mediated mitochondrial biogenesis in cerebral ischemia-reperfusion injury.
Current advances of Mitochondrial dysfunction and cardiovascular disease and promising therapeutic strategies.
Brain MRI detects early-stage alterations and disease progression in Friedreich ataxia.
OPA1 deficiency impacts oxidative metabolism in cycling cells: a translational approach for degenerative diseases.
Metabolic and proteostatic differences in quiescent and active neural stem cells.
Neuroinflammation and Mitochondrial Dysfunction in Parkinson's Disease: Connecting Neuroimaging with Pathophysiology.
Maternal aging increases offspring adult body size via transmission of donut-shaped mitochondria.
Mitochondrial metabolic dysfunction and non-alcoholic fatty liver disease: new insights from pathogenic mechanisms to clinically targeted therapy.
Nonequilibrium thermodynamics and mitochondrial protein content predict insulin sensitivity and fuel selection during exercise in human skeletal muscle.
Cytosolic and mitochondrial translation elongation are coordinated through the molecular chaperone TRAP1 for the synthesis and import of mitochondrial proteins.
NAD+, Axonal Maintenance, and Neurological Disease.

Elife. 2023 Jul 28. pii: e84710. [Epub ahead of print]12

Mitochondrial defects leading to arrested spermatogenesis and ferroptosis in the PARL deficient mouse model of Leigh Syndrome.

Enrico Radaelli, Charles-Antoine Assenmacher, Jillian Verrelle, Esha Banerjee, Florence Manero, Salim Khiati, Anais Girona, Guillermo Lopez-Lluch, Placido Navas, Marco Spinazzi.

  Impaired spermatogenesis and male infertility are common manifestations of mitochondrial diseases, but the underlying mechanisms are unclear. Here we show that mice deficient for the mitochondrial intra-membrane rhomboid protease PARL, a recently reported model of Leigh syndrome, develop early testicular atrophy caused by a complete arrest of spermatogenesis at meiotic prophase I, followed by germ cell death independently of neurodegeneration. Genetic modifications of PINK1, PGAM5, and TTC19, three major substrates of PARL with important roles in mitochondrial homeostasis, do not reproduce or modify this severe phenotype. PARL deficiency in spermatocytes leads to severe abnormalities in mitochondrial structure associated with prominent electron transfer chain defects, alterations in Coenzyme Q (CoQ) biosynthesis, and metabolic rewiring. These mitochondrial defects are associated with a germ-cell specific decrease in GPX4 expression committing arrested spermatocytes to ferroptosis, a regulated cell death modality characterized by uncontrolled lipid peroxidation. Thus, mitochondrial defects, such as those induced by depletion of PARL, spontaneously initiate ferroptosis in primary spermatocytes in vivo by simultaneous effects on GPX4 and CoQ, the two major ferroptosis-inhibitors. Ferroptosis warrants to be further scrutinized in the pathogenesis of mitochondrial diseases and male infertility.

Keywords:  cell biology; mouse

DOI:  https://doi.org/10.7554/eLife.84710
Antioxidants (Basel). 2023 Jul 24. pii: 1477. [Epub ahead of print]12(7):

Complex II Biology in Aging, Health, and Disease.

Eric Goetzman, Zhenwei Gong, Bob Zhang, Radhika Muzumdar.

  Aging is associated with a decline in mitochondrial function which may contribute to age-related diseases such as neurodegeneration, cancer, and cardiovascular diseases. Recently, mitochondrial Complex II has emerged as an important player in the aging process. Mitochondrial Complex II converts succinate to fumarate and plays an essential role in both the tricarboxylic acid (TCA) cycle and the electron transport chain (ETC). The dysfunction of Complex II not only limits mitochondrial energy production; it may also promote oxidative stress, contributing, over time, to cellular damage, aging, and disease. Intriguingly, succinate, the substrate for Complex II which accumulates during mitochondrial dysfunction, has been shown to have widespread effects as a signaling molecule. Here, we review recent advances related to understanding the function of Complex II, succinate signaling, and their combined roles in aging and aging-related diseases.

Keywords:  Complex II; aging; reactive oxygen species; succinate dehydrogenase

DOI:  https://doi.org/10.3390/antiox12071477
J Biol Chem. 2023 Jul 24. pii: S0021-9258(23)02115-4. [Epub ahead of print] 105087

Hyper-ubiquitylation of DNA helicase RECQL4 by E3 ligase MITOL prevents mitochondrial entry and potentiates mitophagy.

Mansoor Hussain, Aftab Mohammed, Shabnam Saifi, Swati Priya, Sagar Sengupta.

  Mutations in the DNA helicase RECQL4 lead to Rothmund-Thomson Syndrome (RTS), a disorder characterized by mitochondrial dysfunctions, premature aging, and genomic instability. However, the mechanisms by which these mutations lead to pathology are unclear. Here we report that RECQL4 is ubiquitylated by a mitochondrial E3 ligase, MITOL, at two lysine residues (K1101, K1154) via K6 linkage. This ubiquitylation hampers the interaction of RECQL4 with mitochondrial importer Tom20, thereby restricting its own entry into mitochondria. We show the RECQL4 2K mutant (where both K1101 and K1154 are mutated) has increased entry into mitochondria and demonstrates enhanced mtDNA replication. We observed that the three tested RTS patient mutants were unable to enter the mitochondria and showed decreased mtDNA replication. Furthermore, we found that RECQL4 in RTS patient mutants are hyper-ubiquitylated by MITOL and form insoluble aggregate-like structures on the outer mitochondrial surface. However, depletion of MITOL allows RECQL4 expressed in these RTS mutants to enter mitochondria and rescue mtDNA replication. Finally, we show increased accumulation of hyper-ubiquitylated RECQL4 outside the mitochondria leads to the cells being potentiated to increased mitophagy. Hence, we conclude regulating the turnover of RECQL4 by MITOL may have a therapeutic effect in RTS patients.

Keywords:  E3 ligases; RecQ helicases; Rothmund Thomson Syndrome; autophagy; mitochondrial replication

DOI:  https://doi.org/10.1016/j.jbc.2023.105087
Adv Exp Med Biol. 2023 ;1429 173-189

Gene Editing Technologies Targeting TFAM and Its Relation to Mitochondrial Diseases.

Vanessa Cristina de Oliveira, Kelly Cristine Santos Roballo, Clesio Gomes Mariano Junior, Carlos Eduardo Ambrósio.

Mitochondria are organelles present in the cytoplasm of eukaryotic cells; they play a key role in adenosine triphosphate (ATP) synthesis and oxidative phosphorylation. Mitochondria have their own DNA, mitochondrial DNA (mtDNA), keeping the function of the mitochondria. Mitochondrial transcription factor A (TFAM) is a member of the HMGB subfamily that binds to mtDNA promoters is and considered essential in mtDNA replication and transcription. More recently, TFAM has been shown to play a central role in the maintenance and regulation of mitochondrial copy number, inflammatory response, expression regulation, and mitochondrial genome activity. Gene editing tools such as the CRISPR-Cas 9 technique, TALENs, and other gene editing tools have been used to investigate the role of TFAM in mitochondrial mechanics and biogenesis as well as its correlation to mitochondrial disorders. Thus this chapter brings a summary of mitochondria function, dysfunction, the importance of TFAM in the maintenance of mitochondria, and state of the art of gene editing tools involving TFAM and mtDNA.

DOI: https://doi.org/10.1007/978-3-031-33325-5_10
EMBO Rep. 2023 Jul 28. e55859

UBQLN2 and HSP70 participate in Parkin-mediated mitophagy by facilitating outer mitochondrial membrane rupture.

Qilian Ma, Jiaqi Xin, Qiang Peng, Ningning Li, Shan Sun, Hongyu Hou, Guoqiang Ma, Nana Wang, Li Zhang, Kin Yip Tam, Heiko Dussmann, Jochen Hm Prehn, Hongfeng Wang, Zheng Ying.

  Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are two aging-related neurodegenerative diseases that share common key features, including aggregation of pathogenic proteins, dysfunction of mitochondria, and impairment of autophagy. Mutations in ubiquilin 2 (UBQLN2), a shuttle protein in the ubiquitin-proteasome system (UPS), can cause ALS/FTD, but the mechanism underlying UBQLN2-mediated pathogenesis is still uncertain. Recent studies indicate that mitophagy, a selective form of autophagy which is crucial for mitochondrial quality control, is tightly associated with neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, and ALS. In this study, we show that after Parkin-dependent ubiquitination of damaged mitochondria, UBQLN2 is recruited to poly-ubiquitinated mitochondria through the UBA domain. UBQLN2 cooperates with the chaperone HSP70 to promote UPS-driven degradation of outer mitochondrial membrane (OMM) proteins. The resulting rupture of the OMM triggers the autophagosomal recognition of the inner mitochondrial membrane receptor PHB2. UBQLN2 is required for Parkin-mediated mitophagy and neuronal survival upon mitochondrial damage, and the ALS/FTD pathogenic mutations in UBQLN2 impair mitophagy in primary cultured neurons. Taken together, our findings link dysfunctional mitophagy to UBQLN2-mediated neurodegeneration.

Keywords:  ALS; Parkin; UBQLN2; mitophagy; ubiquitin

DOI:  https://doi.org/10.15252/embr.202255859
bioRxiv. 2023 Jul 11. pii: 2023.07.11.548601. [Epub ahead of print]

Mitochondrial proteostasis mediated by CRL5 Ozz and Alix maintains skeletal muscle function.

Yvan Campos, Ricardo Rodriguez-Enriquez, Gustavo Palacios, Diantha Van de Vlekkert, Xiaohui Qiu, Jayce Weesner, Elida Gomero, Jeroen Demmers, Tulio Bertorini, Joseph T Opferman, Gerard C Grosveld, Alessandra d'Azzo.

High energy-demanding tissues, such as skeletal muscle, require mitochondrial proteostasis to function properly. Two quality-control mechanisms, the ubiquitin proteasome system (UPS) and the release of mitochondria-derived vesicles, safeguard mitochondrial proteostasis. However, whether these processes interact is unknown. Here we show that the E3 ligase CRL5 Ozz , a member of the UPS, and its substrate Alix control the mitochondrial concentration of Slc25A4, a solute carrier that is essential for ATP production. The mitochondria in Ozz -/- or Alix -/- skeletal muscle share overt morphologic alterations (they are supernumerary, swollen, and dysmorphic) and have abnormal metabolomic profiles. We found that CRL5 Ozz ubiquitinates Slc25A4 and promotes its proteasomal degradation, while Alix facilitates SLC25A4 loading into exosomes destined for lysosomal destruction. The loss of Ozz or Alix offsets steady-state levels of Slc25A4, which disturbs mitochondrial metabolism and alters muscle fiber composition. These findings reveal hitherto unknown regulatory functions of Ozz and Alix in mitochondrial proteostasis.

DOI: https://doi.org/10.1101/2023.07.11.548601
PLoS One. 2023 ;18(7): e0276147

A method to assess the mitochondrial respiratory capacity of complexes I and II from frozen tissue using the Oroboros O2k-FluoRespirometer.

Brad Ebanks, Pola Kwiecinska, Nicoleta Moisoi, Lisa Chakrabarti.

High-resolution respirometry methods allow for the assessment of oxygen consumption by the electron transfer systems within cells, tissue samples, and isolated mitochondrial preparations. As mitochondrial integrity is compromised by the process of cryopreservation, these methods have been limited to fresh samples. Here we present a simple method to assess the activity of mitochondria respiratory complexes I and II in previously cryopreserved murine skeletal muscle tissue homogenates, as well as previously frozen D. melanogaster, as a function of oxygen consumption.

DOI: https://doi.org/10.1371/journal.pone.0276147
Proc Natl Acad Sci U S A. 2023 08;120(31): e2300475120

Nascent mitochondrial proteins initiate the localized condensation of cytosolic protein aggregates on the mitochondrial surface.

Qingqing Liu, Benjamin Fong, Seungmin Yoo, Jay R Unruh, Fengli Guo, Zulin Yu, Jingjing Chen, Kausik Si, Rong Li, Chuankai Zhou.

  Eukaryotes organize cellular contents into membrane-bound organelles and membrane-less condensates, for example, protein aggregates. An unsolved question is why the ubiquitously distributed proteins throughout the cytosol give rise to spatially localized protein aggregates on the organellar surface, like mitochondria. We report that the mitochondrial import receptor Tom70 is involved in the localized condensation of protein aggregates in budding yeast and human cells. This is because misfolded cytosolic proteins do not autonomously aggregate in vivo; instead, they are recruited to the condensation sites initiated by Tom70's substrates (nascent mitochondrial proteins) on the organellar membrane using multivalent hydrophobic interactions. Knocking out Tom70 partially impairs, while overexpressing Tom70 increases the formation and association between cytosolic protein aggregates and mitochondria. In addition, ectopic targeting Tom70 and its substrates to the vacuole surface is able to redirect the localized aggregation from mitochondria to the vacuolar surface. Although other redundant mechanisms may exist, this nascent mitochondrial proteins-based initiation of protein aggregation likely explains the localized condensation of otherwise ubiquitously distributed molecules on the mitochondria. Disrupting the mitochondrial association of aggregates impairs their asymmetric retention during mitosis and reduces the mitochondrial import of misfolded proteins, suggesting a proteostasis role of the organelle-condensate interactions.

Keywords:  condensate; mitochondria; protein aggregation

DOI:  https://doi.org/10.1073/pnas.2300475120
bioRxiv. 2023 Jul 21. pii: 2023.07.20.549963. [Epub ahead of print]

Coenzyme Q 4 is a functional substitute for coenzyme Q 10 and can be targeted to the mitochondria.

Laura H Steenberge, Andrew Y Sung, Jing Fan, David J Pagliarini.

Coenzyme Q 10 (CoQ 10 ) is an important cofactor and antioxidant for numerous cellular processes, and its deficiency has been linked to human disorders including mitochondrial disease, heart failure, Parkinson's disease, and hypertension. Unfortunately, treatment with exogenous oral CoQ 10 is often ineffective, likely due to the extreme hydrophobicity and high molecular weight of CoQ 10 . Here, we show that less hydrophobic CoQ species with shorter isoprenoid tails can serve as viable substitutes for CoQ 10 in human cells. We demonstrate that CoQ 4 can perform multiple functions of CoQ 10 in CoQ-deficient cells at markedly lower treatment concentrations, motivating further investigation of CoQ 4 as a supplement for CoQ 10 deficiencies. In addition, we describe the synthesis and evaluation of an initial set of compounds designed to target CoQ 4 selectively to mitochondria using triphenylphosphonium (TPP). Our results indicate that select versions of these compounds can successfully be delivered to mitochondria in a cell model and be cleaved to produce CoQ 4 , laying the groundwork for further development.

DOI: https://doi.org/10.1101/2023.07.20.549963
Biology (Basel). 2023 Jul 03. pii: 953. [Epub ahead of print]12(7):

A Novel ENU-Induced Mfn2 Mutation Causes Motor Deficits in Mice without Causing Peripheral Neuropathy.

Timothy J Hines, Janice Bailey, Hedi Liu, Anyonya R Guntur, Kevin L Seburn, Samia L Pratt, Jonathan R Funke, Lisa M Tarantino, Robert W Burgess.

  Mitochondrial fission and fusion are required for maintaining functional mitochondria. The mitofusins (MFN1 and MFN2) are known for their roles in mediating mitochondrial fusion. Recently, MFN2 has been implicated in other important cellular functions, such as mitophagy, mitochondrial motility, and coordinating endoplasmic reticulum-mitochondria communication. In humans, over 100 MFN2 mutations are associated with a form of inherited peripheral neuropathy, Charcot-Marie-Tooth disease type 2A (CMT2A). Here we describe an ENU-induced mutant mouse line with a recessive neuromuscular phenotype. Behavioral screening showed progressive weight loss and rapid deterioration of motor function beginning at 8 weeks. Mapping and sequencing revealed a missense mutation in exon 18 of Mfn2 (T1928C; Leu643Pro), within the transmembrane domain. Compared to wild-type and heterozygous littermates, Mfn2L643P/L643P mice exhibited diminished rotarod performance and decreases in activity in the open field test, muscular endurance, mean mitochondrial diameter, sensory tests, mitochondrial DNA content, and MFN2 protein levels. However, tests of peripheral nerve physiology and histology were largely normal. Mutant leg bones had reduced cortical bone thickness and bone area fraction. Together, our data indicate that Mfn2L643P causes a recessive motor phenotype with mild bone and mitochondrial defects in mice. Lack of apparent nerve pathology notwithstanding, this is the first reported mouse model with a mutation in the transmembrane domain of the protein, which may be valuable for researchers studying MFN2 biology.

Keywords:  CMT2A; Charcot–Marie–Tooth disease; mitofusin 2; neuromuscular disease

DOI:  https://doi.org/10.3390/biology12070953
Int J Mol Sci. 2023 Jul 18. pii: 11594. [Epub ahead of print]24(14):

Single Cell Transcriptomic Analysis in a Mouse Model of Barth Syndrome Reveals Cell-Specific Alterations in Gene Expression and Intercellular Communication.

Gayani Perera, Liam Power, Amy Larson, Christina J Codden, Junya Awata, Rebecca Batorsky, Douglas Strathdee, Michael T Chin.

  Barth Syndrome, a rare X-linked disorder affecting 1:300,000 live births, results from defects in Tafazzin, an acyltransferase that remodels cardiolipin and is essential for mitochondrial respiration. Barth Syndrome patients develop cardiomyopathy, muscular hypotonia and cyclic neutropenia during childhood, rarely surviving to middle age. At present, no effective therapy exists, and downstream transcriptional effects of Tafazzin dysfunction are incompletely understood. To identify novel, cell-specific, pathological pathways that mediate heart dysfunction, we performed single-nucleus RNA-sequencing (snRNA-seq) on wild-type (WT) and Tafazzin-knockout (Taz-KO) mouse hearts. We determined differentially expressed genes (DEGs) and inferred predicted cell-cell communication networks from these data. Surprisingly, DEGs were distributed heterogeneously across the cell types, with fibroblasts, cardiomyocytes, endothelial cells, macrophages, adipocytes and pericytes exhibiting the greatest number of DEGs between genotypes. One differentially expressed gene was detected for the lymphatic endothelial and mesothelial cell types, while no significant DEGs were found in the lymphocytes. A Gene Ontology (GO) analysis of these DEGs showed cell-specific effects on biological processes such as fatty acid metabolism in adipocytes and cardiomyocytes, increased translation in cardiomyocytes, endothelial cells and fibroblasts, in addition to other cell-specific processes. Analysis of ligand-receptor pair expression, to infer intercellular communication patterns, revealed the strongest dysregulated communication involved adipocytes and cardiomyocytes. For the knockout hearts, there was a strong loss of ligand-receptor pair expression involving adipocytes, and cardiomyocyte expression of ligand-receptor pairs underwent reorganization. These findings suggest that adipocyte and cardiomyocyte mitochondria may be most sensitive to mitochondrial Tafazzin deficiency and that rescuing adipocyte mitochondrial dysfunction, in addition to cardiomyocyte mitochondrial dysfunction, may provide therapeutic benefit in Barth Syndrome patients.

Keywords:  Barth Syndrome; Tafazzin; cardiomyopathy; gene expression; metabolism; mitochondria; single-nucleus RNA sequencing

DOI:  https://doi.org/10.3390/ijms241411594
Nat Commun. 2023 07 26. 14(1): 4499

A ubiquitin-based effector-to-inhibitor switch coordinates early brain, craniofacial, and skin development.

Anthony J Asmar, Shaun R Abrams, Jenny Hsin, Jason C Collins, Rita M Yazejian, Youmei Wu, Jean Cho, Andrew D Doyle, Samhitha Cinthala, Marleen Simon, Richard H van Jaarsveld, David B Beck, Laura Kerosuo, Achim Werner.

The molecular mechanisms that coordinate patterning of the embryonic ectoderm into spatially distinct lineages to form the nervous system, epidermis, and neural crest-derived craniofacial structures are unclear. Here, biochemical disease-variant profiling reveals a posttranslational pathway that drives early ectodermal differentiation in the vertebrate head. The anteriorly expressed ubiquitin ligase CRL3-KLHL4 restricts signaling of the ubiquitous cytoskeletal regulator CDC42. This regulation relies on the CDC42-activating complex GIT1-βPIX, which CRL3-KLHL4 exploits as a substrate-specific co-adaptor to recognize and monoubiquitylate PAK1. Surprisingly, we find that ubiquitylation converts the canonical CDC42 effector PAK1 into a CDC42 inhibitor. Loss of CRL3-KLHL4 or a disease-associated KLHL4 variant reduce PAK1 ubiquitylation causing overactivation of CDC42 signaling and defective ectodermal patterning and neurulation. Thus, tissue-specific restriction of CDC42 signaling by a ubiquitin-based effector-to-inhibitor is essential for early face, brain, and skin formation, revealing how cell-fate and morphometric changes are coordinated to ensure faithful organ development.

DOI: https://doi.org/10.1038/s41467-023-40223-y
Front Mol Neurosci. 2023 ;16 1224964

Mechanism of PGC-1α-mediated mitochondrial biogenesis in cerebral ischemia-reperfusion injury.

Ying Yuan, Yuan Tian, Hui Jiang, Luo-Yang Cai, Jie Song, Rui Peng, Xiao-Ming Zhang.

  Cerebral ischemia-reperfusion injury (CIRI) is a series of cascade reactions that occur after blood flow recanalization in the ischemic zone in patients with cerebral infarction, causing an imbalance in intracellular homeostasis through multiple pathologies such as increased oxygen free radicals, inflammatory response, calcium overload, and impaired energy metabolism, leading to mitochondrial dysfunction and ultimately apoptosis. Rescue of reversibly damaged neurons in the ischemic hemispheric zone is the key to saving brain infarction and reducing neurological deficits. Complex and active neurological functions are highly dependent on an adequate energy supply from mitochondria. Mitochondrial biogenesis (MB), a process that generates new functional mitochondria and restores normal mitochondrial function by replacing damaged mitochondria, is a major mechanism for maintaining intra-mitochondrial homeostasis and is involved in mitochondrial quality control to ameliorate mitochondrial dysfunction and thus protects against CIRI. The main regulator of MB is peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α), which improves mitochondrial function to protect against CIRI by activating its downstream nuclear respiratory factor 1 (NRF1) and mitochondrial transcription factor A (TFAM) to promote mitochondrial genome replication and transcription. This paper provides a theoretical reference for the treatment of neurological impairment caused by CIRI by discussing the mechanisms of mitochondrial biogenesis during cerebral ischemia-reperfusion injury.

Keywords:  PGC-1α; apoptosis; cerebral ischemia–reperfusion injury; mitochondria; mitochondrial biogenesis

DOI:  https://doi.org/10.3389/fnmol.2023.1224964
Am J Pathol. 2023 Jul 20. pii: S0002-9440(23)00245-6. [Epub ahead of print]

Current advances of Mitochondrial dysfunction and cardiovascular disease and promising therapeutic strategies.

Dexiang Xia, Yue Liu, Peng Wu, Dangheng Wei.

  Mitochondria are "cellular power stations" and essential organelles for maintaining cellular homeostasis. Dysfunctional mitochondria have emerged as a key factor in the occurrence and development of cardiovascular disease. This review focuses on the advances in the relationship between mitochondrial dysfunction and cardiovascular diseases such as atherosclerosis, heart failure, myocardial ischemia reperfusion injury, and pulmonary arterial hypertension. Moreover, the clinical value and challenges of mitochondria-targeted strategies, including mitochondria-targeted antioxidants, mitochondrial quality control modulators, mitochondrial function protectors, mitochondrial biogenesis promoters, and recently developed mitochondrial transplants, are also discussed.

Keywords:  Cardiovascular disease; Mitochondrial dysfunction; Therapeutics

DOI:  https://doi.org/10.1016/j.ajpath.2023.06.013
Brain Commun. 2023 ;5(4): fcad196

Brain MRI detects early-stage alterations and disease progression in Friedreich ataxia.

Isaac M Adanyeguh, James M Joers, Dinesh K Deelchand, Diane H Hutter, Lynn E Eberly, Bin Guo, Isabelle Iltis, Khalaf O Bushara, Pierre-Gilles Henry, Christophe Lenglet.

  Friedreich ataxia is a progressive neurodegenerative disorder characterized by cerebellar and spinal atrophy. However, studies to elucidate the longitudinal progression of the pathology in the brain are somewhat inconsistent and limited, especially for early-stage Friedreich ataxia. Using a multimodal neuroimaging protocol, combined with advanced analysis methods, we sought to identify macrostructural and microstructural alterations in the brain of patients with early-stage Friedreich ataxia to better understand its distribution patterns and progression. We enrolled 28 patients with Friedreich ataxia and 20 age- and gender-matched controls. Longitudinal clinical and imaging data were collected in the patients at baseline, 12, 24 and 36 months. Macrostructural differences were observed in patients with Friedreich ataxia, compared to controls, including lower volume of the cerebellar white matter (but not cerebellar grey matter), superior cerebellar peduncle, thalamus and brainstem structures, and higher volume of the fourth ventricle. Diffusion tensor imaging and fixel-based analysis metrics also showed microstructural differences in several brain regions, especially in the cerebellum and corticospinal tract. Over time, many of these macrostructural and microstructural alterations progressed, especially cerebellar grey and white matter volumes, and microstructure of the superior cerebellar peduncle, posterior limb of the internal capsule and superior corona radiata. In addition, linear regressions showed significant associations between many of those imaging metrics and clinical scales. This study provides evidence of early-stage macrostructural and microstructural alterations and of progression over time in the brain in Friedreich ataxia. Moreover, it allows to non-invasively map such brain alterations over a longer period (3 years) than any previous study, and identifies several brain regions with significant involvement in the disease progression besides the cerebellum. We show that fixel-based analysis of diffusion MRI data is particularly sensitive to longitudinal change in the cerebellar peduncles, as well as motor and sensory white matter tracts. In combination with other morphometric measures, they may therefore provide sensitive imaging biomarkers of disease progression for clinical trials.

Keywords:  diffusion imaging; fixel-based analysis; imaging biomarkers; longitudinal imaging; magnetic resonance imaging

DOI:  https://doi.org/10.1093/braincomms/fcad196
Dis Model Mech. 2023 Jul 27. pii: dmm.050266. [Epub ahead of print]

OPA1 deficiency impacts oxidative metabolism in cycling cells: a translational approach for degenerative diseases.

Aurélie M C Millet, Corentin Coustham, Camille Champigny, Marlène Botella, Christine Demeilliers, Anne Devin, Anne Galinier, Pascale Belenguer, Joel Bordeneuve-Guibé, Noélie Davezac.

  Dominant optic atrophy is an optic neuropathy which displays varying clinical symptoms and progression. A severe disorder is associated with certain OPA1 mutations and includes additional symptoms for more than 20% of patients. This underscores the consequences of OPA1 mutations in different cellular populations, not only retinal ganglionic cells. We assessed the consequences of OPA1 loss of function on oxidative metabolism and antioxidant defences using an RNA silencing strategy in a human epithelial cell line. We observed a decrease of the mitochondrial respiratory chain complexes that was associated with a reduction of aconitase activity related to an increase in reactive oxygen species (ROS) production. In response, the NRF2 transcription factor was translocated into the nucleus and upregulated SOD1 and GSTP1. This paper highlights the effects of OPA1 deficiency on oxidative metabolism in replicative cells, as already shown in neurons. It underlines a translational process to use cycling cells to circumvent and deeply describe the oxidative metabolism. Moreover, it paves the way to predict the evolution of the disease using mathematical models that consider mitochondrial ROS production and their detoxifying pathways.

Keywords:  Mathematical model; Mitochondria; Neurodegenerative disease; Oxidative metabolism

DOI:  https://doi.org/10.1242/dmm.050266
Neural Regen Res. 2024 Jan;19(1): 43-48

Metabolic and proteostatic differences in quiescent and active neural stem cells.

Jiacheng Yu, Gang Chen, Hua Zhu, Yi Zhong, Zhenxing Yang, Zhihong Jian, Xiaoxing Xiong.

  Adult neural stem cells are neurogenesis progenitor cells that play an important role in neurogenesis. Therefore, neural regeneration may be a promising target for treatment of many neurological illnesses. The regenerative capacity of adult neural stem cells can be characterized by two states: quiescent and active. Quiescent adult neural stem cells are more stable and guarantee the quantity and quality of the adult neural stem cell pool. Active adult neural stem cells are characterized by rapid proliferation and differentiation into neurons which allow for integration into neural circuits. This review focuses on differences between quiescent and active adult neural stem cells in nutrition metabolism and protein homeostasis. Furthermore, we discuss the physiological significance and underlying advantages of these differences. Due to the limited number of adult neural stem cells studies, we referred to studies of embryonic adult neural stem cells or non-mammalian adult neural stem cells to evaluate specific mechanisms.

Keywords:  adult neurogenesis; cell metabolic pathway; cellular proliferation; neural stem cell niches; neural stem cells; neuronal differentiation; nutrient sensing pathway; proteostasis

DOI:  https://doi.org/10.4103/1673-5374.375306
Antioxidants (Basel). 2023 Jul 12. pii: 1411. [Epub ahead of print]12(7):

Neuroinflammation and Mitochondrial Dysfunction in Parkinson's Disease: Connecting Neuroimaging with Pathophysiology.

Benjamin Matís Pizarro-Galleguillos, Liesa Kunert, Norbert Brüggemann, Jannik Prasuhn.

  There is a pressing need for disease-modifying therapies in patients suffering from neurodegenerative diseases, including Parkinson's disease (PD). However, these disorders face unique challenges in clinical trial designs to assess the neuroprotective properties of potential drug candidates. One of these challenges relates to the often unknown individual disease mechanisms that would, however, be relevant for targeted treatment strategies. Neuroinflammation and mitochondrial dysfunction are two proposed pathophysiological hallmarks and are considered to be highly interconnected in PD. Innovative neuroimaging methods can potentially help to gain deeper insights into one's predominant disease mechanisms, can facilitate patient stratification in clinical trials, and could potentially map treatment responses. This review aims to highlight the role of neuroinflammation and mitochondrial dysfunction in patients with PD (PwPD). We will specifically introduce different neuroimaging modalities, their respective technical hurdles and challenges, and their implementation into clinical practice. We will gather preliminary evidence for their potential use in PD research and discuss opportunities for future clinical trials.

Keywords:  Parkinson’s disease; TSPO; magnetic resonance imaging (MRI); magnetic resonance spectroscopy imaging (MRSI); mitochondria; mitochondrial dysfunction; neuroimaging; neuroinflammation; positron emission tomography (PET) imaging

DOI:  https://doi.org/10.3390/antiox12071411
Cell Res. 2023 Jul 27.

Maternal aging increases offspring adult body size via transmission of donut-shaped mitochondria.

Runshuai Zhang, Jinan Fang, Ting Qi, Shihao Zhu, Luxia Yao, Guicun Fang, Yunsheng Li, Xiao Zang, Weina Xu, Wanyu Hao, Shouye Liu, Dan Yang, Di Chen, Jian Yang, Xianjue Ma, Lianfeng Wu.

Maternal age at childbearing has continued to increase in recent decades. However, whether and how it influences offspring adult traits are largely unknown. Here, using adult body size as the primary readout, we reveal that maternal rather than paternal age has an evolutionarily conserved effect on offspring adult traits in humans, Drosophila, and Caenorhabditis elegans. Elucidating the mechanisms of such effects in humans and other long-lived animals remains challenging due to their long life course and difficulties in conducting in vivo studies. We thus employ the short-lived and genetically tractable nematode C. elegans to explore the mechanisms underlying the regulation of offspring adult trait by maternal aging. By microscopic analysis, we find that old worms transmit aged mitochondria with a donut-like shape to offspring. These mitochondria are rejuvenated in the offspring's early life, with their morphology fully restored before adulthood in an AMPK-dependent manner. Mechanistically, we demonstrate that early-life mitochondrial dysfunction activates AMPK, which in turn not only alleviates mitochondrial abnormalities but also activates TGFβ signaling to increase offspring adult size. Together, our findings provide mechanistic insight into the ancient role of maternal aging in shaping the traits of adult offspring.

DOI: https://doi.org/10.1038/s41422-023-00854-8
J Transl Med. 2023 Jul 28. 21(1): 510

Mitochondrial metabolic dysfunction and non-alcoholic fatty liver disease: new insights from pathogenic mechanisms to clinically targeted therapy.

Youwei Zheng, Shiting Wang, Jialiang Wu, Yong Wang.

  Metabolic dysfunction-associated fatty liver disease (MAFLD) is among the most widespread metabolic disease globally, and its associated complications including insulin resistance and diabetes have become threatening conditions for human health. Previous studies on non-alcoholic fatty liver disease (NAFLD) were focused on the liver's lipid metabolism. However, growing evidence suggests that mitochondrial metabolism is involved in the pathogenesis of NAFLD to varying degrees in several ways, for instance in cellular division, oxidative stress, autophagy, and mitochondrial quality control. Ultimately, liver function gradually declines as a result of mitochondrial dysfunction. The liver is unable to transfer the excess lipid droplets outside the liver. Therefore, how to regulate hepatic mitochondrial function to treat NAFLD has become the focus of current research. This review provides details about the intrinsic link of NAFLD with mitochondrial metabolism and the mechanisms by which mitochondrial dysfunctions contribute to NAFLD progression. Given the crucial role of mitochondrial metabolism in NAFLD progression, the application potential of multiple mitochondrial function improvement modalities (including physical exercise, diabetic medications, small molecule agonists targeting Sirt3, and mitochondria-specific antioxidants) in the treatment of NAFLD was evaluated hoping to provide new insights into NAFLD treatment.

Keywords:  Lipid metabolism disorders; Mitochondrial division; Mitochondrial quality control; Mitophagy; NAFLD; Oxidative stress; Targeted therapy

DOI:  https://doi.org/10.1186/s12967-023-04367-1
Front Physiol. 2023 ;14 1208186

Nonequilibrium thermodynamics and mitochondrial protein content predict insulin sensitivity and fuel selection during exercise in human skeletal muscle.

Rocio Zapata Bustos, Dawn K Coletta, Jean-Philippe Galons, Lisa B Davidson, Paul R Langlais, Janet L Funk, Wayne T Willis, Lawrence J Mandarino.

  Introduction: Many investigators have attempted to define the molecular nature of changes responsible for insulin resistance in muscle, but a molecular approach may not consider the overall physiological context of muscle. Because the energetic state of ATP (ΔGATP) could affect the rate of insulin-stimulated, energy-consuming processes, the present study was undertaken to determine whether the thermodynamic state of skeletal muscle can partially explain insulin sensitivity and fuel selection independently of molecular changes. Methods: 31P-MRS was used with glucose clamps, exercise studies, muscle biopsies and proteomics to measure insulin sensitivity, thermodynamic variables, mitochondrial protein content, and aerobic capacity in 16 volunteers. Results: After showing calibrated 31P-MRS measurements conformed to a linear electrical circuit model of muscle nonequilibrium thermodynamics, we used these measurements in multiple stepwise regression against rates of insulin-stimulated glucose disposal and fuel oxidation. Multiple linear regression analyses showed 53% of the variance in insulin sensitivity was explained by 1) VO2max (p = 0.001) and the 2) slope of the relationship of ΔGATP with the rate of oxidative phosphorylation (p = 0.007). This slope represents conductance in the linear model (functional content of mitochondria). Mitochondrial protein content from proteomics was an independent predictor of fractional fat oxidation during mild exercise (R2 = 0.55, p = 0.001). Conclusion: Higher mitochondrial functional content is related to the ability of skeletal muscle to maintain a greater ΔGATP, which may lead to faster rates of insulin-stimulated processes. Mitochondrial protein content per se can explain fractional fat oxidation during mild exercise.

Keywords:  31 P-magnetic resonance spectroscopy; exercise; fuel selection; insulin sensitivity; mitochondria; skeletal muscle

DOI:  https://doi.org/10.3389/fphys.2023.1208186
Genome Res. 2023 Jul 24. pii: gr.277755.123. [Epub ahead of print]

Cytosolic and mitochondrial translation elongation are coordinated through the molecular chaperone TRAP1 for the synthesis and import of mitochondrial proteins.

Rosario Avolio, Ilenia Agliarulo, Daniela Criscuolo, Daniela Sarnataro, Margherita Auriemma, Sabrina De Lella, Sara Pennacchio, Giovanni Calice, Martin Y Ng, Carlotta Giorgi, Paolo Pinton, Barry Cooperman, Matteo Landriscina, Franca Esposito, Danilo Swann Matassa.

A complex interplay between mRNA translation and cellular respiration has been recently unveiled, but its regulation in humans is poorly characterized in either health or disease. Cancer cells radically reshape both biosynthetic and bioenergetic pathways to sustain their aberrant growth rates. In this regard, we have shown that the molecular chaperone TRAP1 not only regulates the activity of respiratory complexes, behaving alternatively as an oncogene or a tumor suppressor, but also plays a concomitant moonlighting function in mRNA translation regulation. Herein we identify the molecular mechanisms involved, demonstrating that TRAP1: i) binds both mitochondrial and cytosolic ribosomes as well as translation elongation factors, ii) slows down translation elongation rate, and iii) favors localized translation in the proximity of mitochondria. We also provide evidence that TRAP1 is coexpressed in human tissues with the mitochondrial translational machinery, which is responsible for the synthesis of respiratory complex proteins. Altogether, our results show an unprecedented level of complexity in the regulation of cancer cell metabolism, strongly suggesting the existence of a tight feedback loop between protein synthesis and energy metabolism, based on the demonstration that a single molecular chaperone plays a role in both mitochondrial and cytosolic translation, as well as in mitochondrial respiration.

DOI: https://doi.org/10.1101/gr.277755.123
Antioxid Redox Signal. 2023 Jul 28.

NAD+, Axonal Maintenance, and Neurological Disease.

Athanasios Alexandris, Vassilis E Koliatsos.

SIGNIFICANCE: The remarkable geometry of the axon exposes it to unique challenges for survival and maintenance . Axonal degeneration is a feature of peripheral neuropathies, glaucoma, and traumatic brain injury, and an early event in neurodegenerative diseases. Since the discovery of Wallerian degeneration (WD), a molecular program that hijacks NAD+ metabolism for axonal self-destruction, the complex roles of NAD+ in axonal viability and disease have become research priority.
RECENT ADVANCES: The discoveries of the protective WldS and of SARM1 activation as the main instructive signal for WD have shed new light on the regulatory role of NAD+ in axonal degeneration in a growing number of neurological diseases. SARM1 has been characterized as a NAD+ hydrolase and sensor of NAD+ metabolism. The discovery of regulators of NMNAT2 proteostasis in axons, the allosteric regulation of SARM1 by NAD+ andNMN, and the existence of clinically relevant windows of action of these signals has opened new opportunities for therapeutic interventions, including SARM1 inhibitors and modulators of NAD+ metabolism.
CRITICAL ISSUES: Events upstream and downstream of SARM1 remain unclear. Furthermore, manipulating NAD+ metabolism, an overdetermined process crucial in cell survival, for preventing the degeneration of the injured axon may be difficult and potentially toxic.
FUTURE DIRECTIONS: There is need for clarification of the distinct roles of NAD+ metabolism in axonal maintenance as contrasted to WD. There is also need to better understand the role of NAD+ metabolism in axonal endangerment in neuropathies, diseases of the white matter, and the early stages of CNS neurodegenerative diseases.

DOI: https://doi.org/10.1089/ars.2023.0350