bims-mitmed 2022-07-31 papers

bims-mitmed

Biomed News

on Mitochondrial medicine

Issue of 2022–07–31
43 papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico

Mitophagy: An Emergence of New Player in Alzheimer's Disease.
A molecular dialogue between local translation and mitochondria: powering mitophagy in axons.
Mitigation of age-dependent accumulation of defective mitochondrial genomes.
Respiratory chain dysfunction in perifascicular muscle fibres in patients with dermatomyositis is associated with mitochondrial DNA depletion.
Dichloroacetate improves mitochondrial function, physiology, and morphology in FBXL4 disease models.
Mitochondrial-Dependent and Independent Functions of PINK1.
Metabolic rescue ameliorates mitochondrial encephalo-cardiomyopathy in murine and human iPSC models of Leigh syndrome.
A Novel MTTK Gene Variant m.8315A>C as a Cause of MERRF Syndrome.
Mitochondrial Transfer Between Airway Cells: Helping the Neighbors, or Sending Them Trash?
Cumulus cells mitochondrial dysfunction in advanced-age women.
Activation of the Mitochondrial Unfolded Protein Response: A New Therapeutic Target?
Mitochondrial proteostasis stress in muscle drives a long-range protective response to alleviate dietary obesity independently of ATF4.
Next-Generation Sequencing Identifies Novel PMPCA Variants in Patients with Late-Onset Dominant Optic Atrophy.
Generation of an induced pluripotent stem cell line from a patient with leber's hereditary optic neuropathy carrying a homoplasmic m.3635G > A mutation in the mitochondrial ND1 gene.
Autophagic secretion of mitochondria (ASM): An alternative way for getting rid of damaged mitochondria.
Primary Ovarian Insufficiency in RMND1 Mitochondrial Disease.
Glutamate-Induced Deregulation of Krebs Cycle in Mitochondrial Encephalopathy Lactic Acidosis Syndrome Stroke-Like Episodes (MELAS) Syndrome Is Alleviated by Ketone Body Exposure.
Mitochondrial Calcium-Triggered Oxidative Stress and Developmental Defects in Dopaminergic Neurons Differentiated from Deciduous Teeth-Derived Dental Pulp Stem Cells with MFF Insufficiency.
Dysfunction of Mitochondria in Alzheimer's Disease: ANT and VDAC Interact with Toxic Proteins and Aid to Determine the Fate of Brain Cells.
Mitochondrial control of inflammation.
A Method for In Situ Reverse Genetic Analysis of Proteins Involved mtDNA Replication.
Mitochondrial Elongation and OPA1 Play Crucial Roles during the Stemness Acquisition Process in Pancreatic Ductal Adenocarcinoma.
Mitochondrial Dysfunction Affects the Synovium of Patients with Rheumatoid Arthritis and Osteoarthritis Differently.
Microsporidia Promote Host Mitochondrial Fragmentation by Modulating DRP1 Phosphorylation.
Brain Region and Sex-specific Changes in Mitochondrial Biogenesis Induced by Acute Trimethyltin Exposure.
A Systematic Review of the Impact of Mitochondrial Variations on Male Infertility.
EGFR signaling activates intestinal stem cells by promoting mitochondrial biogenesis and β-oxidation.
Therapeutic vs. Suprapharmacological Metformin Concentrations: Different Effects on Energy Metabolism and Mitochondrial Function in Skeletal Muscle Cells in vitro.
Use of Bisection to Reduce Mitochondrial DNA in the Bovine Oocyte.
Pharmacological sequestration of mitochondrial calcium uptake protects against dementia and β-amyloid neurotoxicity.
Skeletal progenitors preserve proliferation and self-renewal upon inhibition of mitochondrial respiration by rerouting the TCA cycle.
Severe COVID-19 correlates with lower mitochondrial cristae density in PBMCs and greater sitting time in humans.
Differential Susceptibility of Retinal Neurons to the Loss of Mitochondrial Biogenesis Factor Nrf1.
TNK2/ACK1-mediated phosphorylation of ATP5F1A (ATP synthase F1 subunit alpha) selectively augments survival of prostate cancer while engendering mitochondrial vulnerability.
Targeting skeletal muscle mitochondrial health in obesity.
Oxidative Stress in Tauopathies: From Cause to Therapy.
Primary and Secondary Mitochondrial Diseases: Etiologies and Therapeutic Strategies.
Evidence of impaired mitochondrial cellular bioenergetics in ocular fibroblasts derived from glaucoma patients.
Catalytic cycling of human mitochondrial Lon protease.
NAD+ Precursors: A Questionable Redundancy.
Mitochondria Transfer from Adipose Stem Cells Improves the Developmental Potential of Cryopreserved Oocytes.
In Vitro Efficacy and Molecular Mechanism of Curcumin Analog in Pathological Regulation of Spinocerebellar Ataxia Type 3.
Epigenetic control of mitochondrial fission enables hepatic stellate cells activation in liver fibrosis via PGC-1α-Drp1 pathway.

Front Mol Neurosci. 2022 ;15 921908

Mitophagy: An Emergence of New Player in Alzheimer's Disease.

Bunty Sharma, Deeksha Pal, Ujjawal Sharma, Aman Kumar.

  Mitochondria provide neurons not only energy as ATP to keep them growing, proliferating and developing, but they also control apoptosis. Due to their high bioenergetic demand, neurons which are highly specific terminally differentiated cells, essentially depend on mitochondria. Defective mitochondrial function is thus related to numerous age-linked neurodegenerative ailments like Alzheimer's disease (AD), in which the build-up of impaired and malfunctioning mitochondria has been identified as a primary sign, paying to disease development. Mitophagy, selective autophagy, is a key mitochondrial quality control system that helps neurons to stay healthy and functional by removing undesired and damaged mitochondria. Dysfunctional mitochondria and dysregulated mitophagy have been closely associated with the onset of ADs. Various proteins associated with mitophagy were found to be altered in AD. Therapeutic strategies focusing on the restoration of mitophagy capabilities could be utilized to strike the development of AD pathogenesis. We summarize the mechanism and role of mitophagy in the onset and advancement of AD, in the quality control mechanism of mitochondria, the consequences of dysfunctional mitophagy in AD, and potential therapeutic approaches involving mitophagy modulation in AD. To develop new therapeutic methods, a better knowledge of the function of mitophagy in the pathophysiology of AD is required.

Keywords:  Alzheimer’s disease; mitochondrial dynamics; mitochondrial dysfunction; mitochondrial quality control; mitophagy; targeting mitophagy

DOI:  https://doi.org/10.3389/fnmol.2022.921908
Mol Biol Rep. 2022 Jul 28.

A molecular dialogue between local translation and mitochondria: powering mitophagy in axons.

Andrea Soumbasis, Mohamed A Eldeeb.

  Mitochondrial quality control is a key element of neuronal health and viability. When left untouched, defective mitochondria can initiate neuronal degeneration. Cytosolic proteins PINK1 and Parkin comprise one key pathway responsible for clearing damaged mitochondria. Neurons, however, pose a unique challenge to this process because proteins need to be abundantly available at locations distant from the cell body. Recent study has confirmed that local translation of PINK1 in axons and dendrites is the solution. Pink1 transcripts are tethered to mitochondria via SYNJ2a and active translation, then subsequently co-transported to distal locations. Once arriving in the neuron's periphery, local translation of PINK1 can facilitate mitophagy and ultimately sustain mitochondrial health.

Keywords:  Local translation; Mitochondrial quality control; Mitophagy; PINK1; Parkinson; Protein quality control

DOI:  https://doi.org/10.1007/s11033-022-07708-3
Proc Natl Acad Sci U S A. 2022 Aug 02. 119(31): e2119009119

Mitigation of age-dependent accumulation of defective mitochondrial genomes.

Pei-I Tsai, Ekaterina Korotkevich, Patrick H O'Farrell.

  Unknown processes promote the accumulation of mitochondrial DNA (mtDNA) mutations during aging. Accumulation of defective mitochondrial genomes is thought to promote the progression of heteroplasmic mitochondrial diseases and degenerative changes with natural aging. We used a heteroplasmic Drosophila model to test 1) whether purifying selection acts to limit the abundance of deleterious mutations during development and aging, 2) whether quality control pathways contribute to purifying selection, 3) whether activation of quality control can mitigate accumulation of deleterious mutations, and 4) whether improved quality control improves health span. We show that purifying selection operates during development and growth but is ineffective during aging. Genetic manipulations suggest that a quality control process known to enforce purifying selection during oogenesis also suppresses accumulation of a deleterious mutation during growth and development. Flies with nuclear genotypes that enhance purifying selection sustained higher genome quality, retained more vigorous climbing activity, and lost fewer dopaminergic neurons. A pharmacological agent thought to enhance quality control produced similar benefits. Importantly, similar pharmacological treatment of aged mice reversed age-associated accumulation of a deleterious mtDNA mutation. Our findings reveal dynamic maintenance of mitochondrial genome fitness and reduction in the effectiveness of purifying selection during life. Importantly, we describe interventions that mitigate and even reverse age-associated genome degeneration in flies and in mice. Furthermore, mitigation of genome degeneration improved well-being in a Drosophila model of heteroplasmic mitochondrial disease.

Keywords:  aging; heteroplasmy; mitochondria; mtDNA; mutations

DOI:  https://doi.org/10.1073/pnas.2119009119
Neuropathol Appl Neurobiol. 2022 Jul 27. e12841

Respiratory chain dysfunction in perifascicular muscle fibres in patients with dermatomyositis is associated with mitochondrial DNA depletion.

Carola Hedberg-Oldfors, Ulrika Lindgren, Kittichate Visuttijai, Daniel Lööf, Sara Roos, Christer Thomsen, Anders Oldfors.

   AIMS: Patients with dermatomyositis suffer from reduced aerobic metabolism contributing to impaired muscle function, which has been linked to cytochrome c oxidase (COX) deficiency in muscle tissue. This mitochondrial respiratory chain dysfunction is typically seen in perifascicular regions, which also show the most intense inflammatory reaction along with capillary loss and muscle fibre atrophy. The objective of this study was to investigate the pathobiology of the oxidative phosphorylation deficiency in dermatomyositis.
METHODS: Muscle biopsy specimens with perifascicular COX deficiency from five juveniles and seven adults with dermatomyositis were investigated. We combined immunohistochemical analyses of subunits in the respiratory chain including complex I (subunit NDUFB8), complex II (succinate dehydrogenase, subunit SDHB) and complex IV (COX, subunit MTCO1) with in situ hybridization, next generation deep sequencing and quantitative PCR.
RESULTS: There was a profound deficiency of complexes I and IV in the perifascicular regions with enzyme histochemical COX deficiency, whereas succinate dehydrogenase activity and complex II were preserved. In situ hybridization of mitochondrial RNA showed depletion of mitochondrial DNA (mtDNA) transcripts in the perifascicular regions. Analysis of mtDNA by next generation deep sequencing and quantitative PCR in affected muscle regions showed an overall reduction of mtDNA copy number particularly in the perifascicular regions.
CONCLUSION: The respiratory chain dysfunction in dermatomyositis muscle is associated with mtDNA depletion causing deficiency of complexes I and IV, which are partially encoded by mtDNA, whereas complex II, which is entirely encoded by nuclear DNA is preserved. The depletion of mtDNA indicates a perturbed replication of mtDNA explaining the muscle pathology and the disturbed aerobic metabolism.

Keywords:  dermatomyositis; inflammatory myopathy; mitochondria; mitochondrial DNA; oxidative phosphorylation; respiratory chain

DOI:  https://doi.org/10.1111/nan.12841
JCI Insight. 2022 Jul 26. pii: e156346. [Epub ahead of print]

Dichloroacetate improves mitochondrial function, physiology, and morphology in FBXL4 disease models.

Manuela Lavorato, Eiko Nakamaru-Ogiso, Neal D Mathew, Elizabeth Herman, Nina K Shah, Suraiya Haroon, Rui Xiao, Christoph Seiler, Marni J Falk.

  Pathogenic variants in the human F Box and Leucine Rich Repeat Protein 4 (FBXL4) gene result in an autosomal recessive, multi-systemic, mitochondrial disorder involving variable mitochondrial depletion and respiratory chain (RC) complex deficiencies with lactic acidemia. As no FDA-approved effective therapies exist, we sought to characterize translational C. elegans and zebrafish animal models, as well as human fibroblasts, to study FBXL4-/- disease mechanisms and identify preclinical therapeutic leads. Developmental delay, impaired fecundity and neurologic and/or muscular activity, mitochondrial dysfunction, and altered lactate metabolism were identified in fbxl-1(ok3741) C. elegans. Detailed studies of a pyruvate dehydrogenase complex activator, dichloroacetate (DCA) in fbxl-1(ok3741) C. elegans demonstrated its beneficial effects on fecundity, neuromotor activity, and mitochondrial function. Validation studies were performed in fbxl4sa12470 zebrafish larvae and in FBXL4-/- human fibroblasts, which showed DCA efficacy in preventing brain damage, impairment of neurologic and/or muscular function, mitochondrial biochemical dysfunction, and stress-induced morphologic and ultrastructural mitochondrial defects. These data demonstrate that fbxl-1 (ok3741) C. elegans and fbxl4sa12470 zebrafish provide robust translational models to study mechanisms and identify preclinical therapeutic candidates for FBXL4-/- disease. Further, DCA is a lead therapeutic candidate with therapeutic benefit on diverse aspects of survival, neurologic and/or muscular function, and mitochondrial physiology that warrants rigorous clinical trial study in human subjects with FBXL4-/- disease.

Keywords:  Drug therapy; Genetic diseases; Genetics; Metabolism; Mitochondria

DOI:  https://doi.org/10.1172/jci.insight.156346
Front Cell Dev Biol. 2022 ;10 954536

Mitochondrial-Dependent and Independent Functions of PINK1.

Xiusheng Chen, Qi Wang, Shihua Li, Xiao-Jiang Li, Weili Yang.

  PINK1 has been characterized as a mitochondrial kinase that can target to damaged mitochondria to initiate mitophagy, a process to remove unhealthy mitochondria for protecting neuronal cells. Mutations of the human PINK1 gene are also found to cause early onset Parkinson's disease, a neurodegenerative disorder with the pathological feature of mitochondrial dysfunction. Despite compelling evidence from in vitro studies to support the role of PINK1 in regulation of mitochondrial function, there is still lack of strong in vivo evidence to validate PINK1-mediated mitophagy in the brain. In addition, growing evidence indicates that PINK1 also executes function independent of mitochondria. In this review, we discuss the mitochondrial dependent and independent functions of PINK1, aiming at elucidating how PINK1 functions differentially under different circumstances.

Keywords:  PINK1; Parkinson’s disease (PD); mitochondria; mitophagy; parkin (PARK2)

DOI:  https://doi.org/10.3389/fcell.2022.954536
Clin Transl Med. 2022 Jul;12(7): e954

Metabolic rescue ameliorates mitochondrial encephalo-cardiomyopathy in murine and human iPSC models of Leigh syndrome.

Jin-Young Yoon, Nastaran Daneshgar, Yi Chu, Biyi Chen, Marco Hefti, Ajit Vikram, Kaikobad Irani, Long-Sheng Song, Charles Brenner, E Dale Abel, Barry London, Dao-Fu Dai.

   BACKGROUND: Mice with deletion of complex I subunit Ndufs4 develop mitochondrial encephalomyopathy resembling Leigh syndrome (LS). The metabolic derangement and underlying mechanisms of cardio-encephalomyopathy in LS remains incompletely understood.
METHODS: We performed echocardiography, electrophysiology, confocal microscopy, metabolic and molecular/morphometric analysis of the mice lacking Ndufs4. HEK293 cells, human iPS cells-derived cardiomyocytes and neurons were used to determine the mechanistic role of mitochondrial complex I deficiency.
RESULTS: LS mice develop severe cardiac bradyarrhythmia and diastolic dysfunction. Human-induced pluripotent stem cell-derived cardiomyocytes (iPS-CMs) with Ndufs4 deletion recapitulate LS cardiomyopathy. Mechanistically, we demonstrate a direct link between complex I deficiency, decreased intracellular (nicotinamide adenine dinucleotide) NAD+ /NADH and bradyarrhythmia, mediated by hyperacetylation of the cardiac sodium channel NaV 1.5, particularly at K1479 site. Neuronal apoptosis in the cerebellar and midbrain regions in LS mice was associated with hyperacetylation of p53 and activation of microglia. Targeted metabolomics revealed increases in several amino acids and citric acid cycle intermediates, likely due to impairment of NAD+ -dependent dehydrogenases, and a substantial decrease in reduced Glutathione (GSH). Metabolic rescue by nicotinamide riboside (NR) supplementation increased intracellular NAD+ / NADH, restored metabolic derangement, reversed protein hyperacetylation through NAD+ -dependent Sirtuin deacetylase, and ameliorated cardiomyopathic phenotypes, concomitant with improvement of NaV 1.5 current and SERCA2a function measured by Ca2+ -transients. NR also attenuated neuronal apoptosis and microglial activation in the LS brain and human iPS-derived neurons with Ndufs4 deletion.
CONCLUSIONS: Our study reveals direct mechanistic explanations of the observed cardiac bradyarrhythmia, diastolic dysfunction and neuronal apoptosis in mouse and human induced pluripotent stem cells (iPSC) models of LS.

Keywords:  Cardio-encephalomyopathy; Leigh syndrome; Ndufs; mitochondria; nicotinamide riboside

DOI:  https://doi.org/10.1002/ctm2.954
Genes (Basel). 2022 Jul 14. pii: 1245. [Epub ahead of print]13(7):

A Novel MTTK Gene Variant m.8315A>C as a Cause of MERRF Syndrome.

Hana Štufková, Hana Kolářová, Kateřina Lokvencová, Tomáš Honzík, Jiří Zeman, Hana Hansíková, Markéta Tesařová.

  In this study, we report on a novel heteroplasmic pathogenic variant in mitochondrial DNA (mtDNA). The studied patient had myoclonus, epilepsy, muscle weakness, and hearing impairment and harbored a heteroplasmic m.8315A>C variant in the MTTK gene with a mutation load ranging from 71% to >96% in tested tissues. In muscle mitochondria, markedly decreased activities of respiratory chain complex I + III and complex IV were observed together with mildly reduced amounts of complex I and complex V (with the detection of V*- and free F1-subcomplexes) and a diminished level of complex IV holoenzyme. This pattern was previously seen in other MTTK pathogenic variants. The novel variant was not present in internal and publicly available control databases. Our report further expands the spectrum of MTTK variants associated with mitochondrial encephalopathies in adults.

Keywords:  MTTK gene; OXPHOS; heteroplasmy; m.8315A>C; mtDNA

DOI:  https://doi.org/10.3390/genes13071245
Am J Respir Cell Mol Biol. 2022 Jul 26.

Mitochondrial Transfer Between Airway Cells: Helping the Neighbors, or Sending Them Trash?

Jazmin Calyeca, Ana L Mora.



Keywords:  Airway smooth muscle cell; COPD; Intercellular mitochondrial transfer; Mitochondria; Transmitophagy

DOI:  https://doi.org/10.1165/rcmb.2022-0265ED
Fertil Steril. 2022 Aug;pii: S0015-0282(22)00406-X. [Epub ahead of print]118(2): 405-406

Cumulus cells mitochondrial dysfunction in advanced-age women.

Mónica Hebe Vazquez-Levin.

DOI: https://doi.org/10.1016/j.fertnstert.2022.06.024
Biomedicines. 2022 Jul 06. pii: 1611. [Epub ahead of print]10(7):

Activation of the Mitochondrial Unfolded Protein Response: A New Therapeutic Target?

Juan M Suárez-Rivero, Carmen J Pastor-Maldonado, Suleva Povea-Cabello, Mónica Álvarez-Córdoba, Irene Villalón-García, Marta Talaverón-Rey, Alejandra Suárez-Carrillo, Manuel Munuera-Cabeza, Diana Reche-López, Paula Cilleros-Holgado, Rocío Piñero-Pérez, José A Sánchez-Alcázar.

  Mitochondrial dysfunction is a key hub that is common to many diseases. Mitochondria's role in energy production, calcium homeostasis, and ROS balance makes them essential for cell survival and fitness. However, there are no effective treatments for most mitochondrial and related diseases to this day. Therefore, new therapeutic approaches, such as activation of the mitochondrial unfolded protein response (UPRmt), are being examined. UPRmt englobes several compensation processes related to proteostasis and antioxidant mechanisms. UPRmt activation, through an hormetic response, promotes cell homeostasis and improves lifespan and disease conditions in biological models of neurodegenerative diseases, cardiopathies, and mitochondrial diseases. Although UPRmt activation is a promising therapeutic option for many conditions, its overactivation could lead to non-desired side effects, such as increased heteroplasmy of mitochondrial DNA mutations or cancer progression in oncologic patients. In this review, we present the most recent UPRmt activation therapeutic strategies, UPRmt's role in diseases, and its possible negative consequences in particular pathological conditions.

Keywords:  aging; heart diseases; homeostasis; lifespan; mitochondria; mitochondrial diseases; neurodegeneration; proteostasis; therapeutic target; unfolded protein response

DOI:  https://doi.org/10.3390/biomedicines10071611
Sci Adv. 2022 Jul 29. 8(30): eabo0340

Mitochondrial proteostasis stress in muscle drives a long-range protective response to alleviate dietary obesity independently of ATF4.

Qiqi Guo, Zhisheng Xu, Danxia Zhou, Tingting Fu, Wen Wang, Wanping Sun, Liwei Xiao, Lin Liu, Chenyun Ding, Yujing Yin, Zheng Zhou, Zongchao Sun, Yuangang Zhu, Wenjing Zhou, Yuhuan Jia, Jiachen Xue, Yuncong Chen, Xiao-Wei Chen, Hai-Long Piao, Bin Lu, Zhenji Gan.

Mitochondrial quality in skeletal muscle is crucial for maintaining energy homeostasis during metabolic stresses. However, how muscle mitochondrial quality is controlled and its physiological impacts remain unclear. Here, we demonstrate that mitoprotease LONP1 is essential for preserving muscle mitochondrial proteostasis and systemic metabolic homeostasis. Skeletal muscle-specific deletion of Lon protease homolog, mitochondrial (LONP1) impaired mitochondrial protein turnover, leading to muscle mitochondrial proteostasis stress. A benefit of this adaptive response was the complete resistance to diet-induced obesity. These favorable metabolic phenotypes were recapitulated in mice overexpressing LONP1 substrate ΔOTC in muscle mitochondria. Mechanistically, mitochondrial proteostasis imbalance elicits an unfolded protein response (UPRmt) in muscle that acts distally to modulate adipose tissue and liver metabolism. Unexpectedly, contrary to its previously proposed role, ATF4 is dispensable for the long-range protective response of skeletal muscle. Thus, these findings reveal a pivotal role of LONP1-dependent mitochondrial proteostasis in directing muscle UPRmt to regulate systemic metabolism.

DOI: https://doi.org/10.1126/sciadv.abo0340
Genes (Basel). 2022 Jul 05. pii: 1202. [Epub ahead of print]13(7):

Next-Generation Sequencing Identifies Novel PMPCA Variants in Patients with Late-Onset Dominant Optic Atrophy.

Majida Charif, Arnaud Chevrollier, Naïg Gueguen, Selma Kane, Céline Bris, David Goudenège, Valerie Desquiret-Dumas, Isabelle Meunier, Fanny Mochel, Luc Jeanjean, Fanny Varenne, Vincent Procaccio, Pascal Reynier, Dominique Bonneau, Patrizia Amati-Bonneau, Guy Lenaers.

  Dominant Optic Atrophy (DOA) is one of the most common inherited mitochondrial diseases, leading to blindness. It is caused by the chronic degeneration of the retinal ganglion cells (RGCs) and their axons forming the optic nerve. Until now, DOA has been mainly associated with genes encoding proteins involved in mitochondrial network dynamics. Using next-generation and exome sequencing, we identified for the first time heterozygous PMPCA variants having a causative role in the pathology of late-onset primary DOA in five patients. PMPCA encodes an α subunit of the mitochondrial peptidase (MPP), responsible for the cleavage and maturation of the mitochondrial precursor proteins imported from the cytoplasm into mitochondria. Recently, PMPCA has been identified as the gene responsible for Autosomal Recessive Cerebellar Ataxia type 2 (SCAR2) and another severe recessive mitochondrial disease. In this study, four PMPCA variants were identified, two are frameshifts (c.309delA and c.820delG) classified as pathogenic and two are missenses (c.1363G>A and c.1547G>A) classified with uncertain pathological significance. Functional assays on patients' fibroblasts show a hyperconnection of the mitochondrial network and revealed that frameshift variants reduced α-MPP levels, while not significantly affecting the respiratory machinery. These results suggest that alterations in mitochondrial peptidase function can affect the fusion-fission balance, a key element in maintaining the physiology of retinal ganglion cells, and consequently lead to their progressive degeneration.

Keywords:  dominant optic atrophy; heterozygous variants; mitochondrial dynamic; mitochondrial peptidase; retinal ganglion cell degeneration

DOI:  https://doi.org/10.3390/genes13071202
Stem Cell Res. 2022 Jul 12. pii: S1873-5061(22)00207-0. [Epub ahead of print]63 102858

Generation of an induced pluripotent stem cell line from a patient with leber's hereditary optic neuropathy carrying a homoplasmic m.3635G > A mutation in the mitochondrial ND1 gene.

Dongmei Ji, Xun Su, Chao Hu, Zhikang Zhang, Mengyao Wang, Weiwei Zou, Lingchao Shen, Yajing Liu, Chunmei Liang, Yinan Du, Dan Liang, Yunxia Cao.

Leber's hereditary optic neuropathy (LHON) is a mitochondrial disease that usually leads to selective degeneration of retinal ganglion cells (RGCs) and optic atrophy in young adults. One of three common mitochondrial DNA (mtDNA) mutations (m.11778G > A, m.3460G > A, m.14484 T > C) account for 90% of LHON cases. All three affect the function of respiration chain complex I. However, m.3635G > A, affecting the structure and function of MT-ND1 gene, is also associated with LHON. Here, we successfully generated a human induced pluripotent stem cell (hiPSC) line from an LHON patient carrying a homoplasmic m.3635G > A mutation in the MT-ND1 gene.

DOI: https://doi.org/10.1016/j.scr.2022.102858
Autophagy. 2022 Jul 28.

Autophagic secretion of mitochondria (ASM): An alternative way for getting rid of damaged mitochondria.

Hayden Weng Siong Tan, Guang Lu, Han-Ming Shen.

  PINK1-PRKN/Parkin-mediated mitophagy represents an important mitochondrial quality control (MQC) pathway that clears damaged/dysfunctional mitochondria. Although the conjugation of mammalian Atg8-family proteins (mATG8s) to phosphatidylethanolamine (PE) is a defining step in autophagy, its role in mitophagy remains unclear. In our recent study, we found that the mATG8 conjugation system is not required for PINK1-PRKN-mediated mitochondria clearance. Instead, mATG8 conjugation system-independent mitochondria clearance relies on secretory autophagy, in a process we term as the autophagic secretion of mitochondria (ASM). As ASM results in the spurious activation of the CGAS-STING1 pathway, we propose that defects in mATG8 lipidation may promote inflammation through ASM.

Keywords:  Extracellular vesicles; PINK1-PRKN; inflammation; mATG8 conjugation system; mitochondrial quality control; mitophagy; secretory autophagy

DOI:  https://doi.org/10.1080/15548627.2022.2107310
Mitochondrion. 2022 Jul 25. pii: S1567-7249(22)00060-5. [Epub ahead of print]

Primary Ovarian Insufficiency in RMND1 Mitochondrial Disease.

E Boros, F Elilié Mawa Ongoth, C Heinrichs, A L Mansbach, S Seneca, A Aeby, K Ismaïli, C Brachet.

  RMND1 (Required for Meiotic Nuclear Division 1 homolog) is a nuclear encoded mitochondrial protein. Biallelic variants inRMND1are described in patients with white matter encephalopathy, hearing loss and renal dysfunction. In addition to this phenotype, two independent families (3 patients) have been reported with ovarian failure. We report on a 17-year-old girl with RMND1 related mitochondrial disorder including white matter encephalopathy, hearing loss and renal insufficiency who presented primary ovarian insufficiency in whom a homozygous variant c.713 A>G (p.Asn238Ser) in the RMND1 gene was found. We report the fourth patient with RMND1 biallelic pathogenic variants and primary ovarian insufficiency.

Keywords:  Mitochondria; Ovarian Failure; Perrault syndrome; Primary Ovarian Insufficiency; RMND1

DOI:  https://doi.org/10.1016/j.mito.2022.07.004
Biomedicines. 2022 Jul 11. pii: 1665. [Epub ahead of print]10(7):

Glutamate-Induced Deregulation of Krebs Cycle in Mitochondrial Encephalopathy Lactic Acidosis Syndrome Stroke-Like Episodes (MELAS) Syndrome Is Alleviated by Ketone Body Exposure.

Sophie Belal, David Goudenège, Cinzia Bocca, Florent Dumont, Juan Manuel Chao De La Barca, Valérie Desquiret-Dumas, Naïg Gueguen, Guillaume Geffroy, Rayane Benyahia, Selma Kane, Salim Khiati, Céline Bris, Tamas Aranyi, Daniel Stockholm, Aurore Inisan, Aurélie Renaud, Magalie Barth, Gilles Simard, Pascal Reynier, Franck Letournel, Guy Lenaers, Dominique Bonneau, Arnaud Chevrollier, Vincent Procaccio.

  (1) Background: The development of mitochondrial medicine has been severely impeded by a lack of effective therapies. (2) Methods: To better understand Mitochondrial Encephalopathy Lactic Acidosis Syndrome Stroke-like episodes (MELAS) syndrome, neuronal cybrid cells carrying different mutation loads of the m.3243A > G mitochondrial DNA variant were analysed using a multi-omic approach. (3) Results: Specific metabolomic signatures revealed that the glutamate pathway was significantly increased in MELAS cells with a direct correlation between glutamate concentration and the m.3243A > G heteroplasmy level. Transcriptomic analysis in mutant cells further revealed alterations in specific gene clusters, including those of the glutamate, gamma-aminobutyric acid pathways, and tricarboxylic acid (TCA) cycle. These results were supported by post-mortem brain tissue analysis from a MELAS patient, confirming the glutamate dysregulation. Exposure of MELAS cells to ketone bodies significantly reduced the glutamate level and improved mitochondrial functions, reducing the accumulation of several intermediate metabolites of the TCA cycle and alleviating the NADH-redox imbalance. (4) Conclusions: Thus, a multi-omic integrated approach to MELAS cells revealed glutamate as a promising disease biomarker, while also indicating that a ketogenic diet should be tested in MELAS patients.

Keywords:  MELAS syndrome; NADH/NAD imbalance; glutamate; ketone body treatment; mitochondrial diseases; mtDNA; multi-omics; tricarboxylic acid cycle

DOI:  https://doi.org/10.3390/biomedicines10071665
Antioxidants (Basel). 2022 Jul 13. pii: 1361. [Epub ahead of print]11(7):

Mitochondrial Calcium-Triggered Oxidative Stress and Developmental Defects in Dopaminergic Neurons Differentiated from Deciduous Teeth-Derived Dental Pulp Stem Cells with MFF Insufficiency.

Xiao Sun, Shuangshan Dong, Hiroki Kato, Jun Kong, Yosuke Ito, Yuta Hirofuji, Hiroshi Sato, Takahiro A Kato, Yasunari Sakai, Shouichi Ohga, Satoshi Fukumoto, Keiji Masuda.

  Mitochondrial fission factor (MFF) is an adapter that targets dynamin-related protein 1 from the cytosol to the mitochondria for fission. Loss-of-function MFF mutations cause encephalopathy due to defective mitochondrial and peroxisomal fission 2 (EMPF2). To elucidate the molecular mechanisms that were involved, we analyzed the functional effects of MFF depletion in deciduous teeth-derived dental pulp stem cells differentiating into dopaminergic neurons (DNs). When treated with MFF-targeting small interfering RNA, DNs showed impaired neurite outgrowth and reduced mitochondrial signals in neurites harboring elongated mitochondria. MFF silencing also caused mitochondrial Ca2+ accumulation through accelerated Ca2+ influx from the endoplasmic reticulum (ER) via the inositol 1,4,5-trisphosphate receptor. Mitochondrial Ca2+ overload led DNs to produce excessive reactive oxygen species (ROS), and downregulated peroxisome proliferator-activated receptor-gamma co-activator-1 alpha (PGC-1α). MFF was co-immunoprecipitated with voltage-dependent anion channel 1, an essential component of the ER-mitochondrial Ca2+ transport system. Folic acid supplementation normalized ROS levels, PGC-1α mediated mitochondrial biogenesis, and neurite outgrowth in MFF depleted DNs, without affecting their mitochondrial morphology or Ca2+ levels. We propose that MFF negatively regulates the mitochondrial Ca2+ influx from the ER. MFF-insufficiency recapitulated the EMPF2 neuropathology with increased oxidative stress and suppressed mitochondrial biogenesis. ROS and mitochondrial biogenesis might be potential therapeutic targets for EMPF2.

Keywords:  EMPF2; mitochondrial calcium; mitochondrial fission factor; reactive oxygen species; stem cells from human exfoliated deciduous teeth

DOI:  https://doi.org/10.3390/antiox11071361
Int J Mol Sci. 2022 Jul 13. pii: 7722. [Epub ahead of print]23(14):

Dysfunction of Mitochondria in Alzheimer's Disease: ANT and VDAC Interact with Toxic Proteins and Aid to Determine the Fate of Brain Cells.

Anna Atlante, Daniela Valenti, Valentina Latina, Giuseppina Amadoro.

  Alzheimer's disease (AD), certainly the most widespread proteinopathy, has as classical neuropathological hallmarks, two groups of protein aggregates: senile plaques and neurofibrillary tangles. However, the research interest is rapidly gaining ground in a better understanding of other pathological features, first, of all the mitochondrial dysfunctions. Several pieces of evidence support the hypothesis that abnormal mitochondrial function may trigger aberrant processing of amyloid progenitor protein or tau and thus neurodegeneration. Here, our aim is to emphasize the role played by two 'bioenergetic' proteins inserted in the mitochondrial membranes, inner and outer, respectively, that is, the adenine nucleotide translocator (ANT) and the voltage-dependent anion channel (VDAC), in the progression of AD. To perform this, we will magnify the ANT and VDAC defects, which are measurable hallmarks of mitochondrial dysfunction, and collect all the existing information on their interaction with toxic Alzheimer's proteins. The pathological convergence of tau and amyloid β-peptide (Aβ) on mitochondria may finally explain why the therapeutic strategies used against the toxic forms of Aβ or tau have not given promising results separately. Furthermore, the crucial role of ANT-1 and VDAC impairment in the onset/progression of AD opens a window for new therapeutic strategies aimed at preserving/improving mitochondrial function, which is suspected to be the driving force leading to plaque and tangle deposition in AD.

Keywords:  Alzheimer’s disease; VDAC; adenine nucleotide translocator; amyloid β-peptide; mitochondria; mitochondrial respiratory chain; tau

DOI:  https://doi.org/10.3390/ijms23147722
Nat Rev Immunol. 2022 Jul 25.

Mitochondrial control of inflammation.

Saverio Marchi, Emma Guilbaud, Stephen W G Tait, Takahiro Yamazaki, Lorenzo Galluzzi.

Numerous mitochondrial constituents and metabolic products can function as damage-associated molecular patterns (DAMPs) and promote inflammation when released into the cytosol or extracellular milieu. Several safeguards are normally in place to prevent mitochondria from eliciting detrimental inflammatory reactions, including the autophagic disposal of permeabilized mitochondria. However, when the homeostatic capacity of such systems is exceeded or when such systems are defective, inflammatory reactions elicited by mitochondria can become pathogenic and contribute to the aetiology of human disorders linked to autoreactivity. In addition, inefficient inflammatory pathways induced by mitochondrial DAMPs can be pathogenic as they enable the establishment or progression of infectious and neoplastic disorders. Here we discuss the molecular mechanisms through which mitochondria control inflammatory responses, the cellular pathways that are in place to control mitochondria-driven inflammation and the pathological consequences of dysregulated inflammatory reactions elicited by mitochondrial DAMPs.

DOI: https://doi.org/10.1038/s41577-022-00760-x
Cells. 2022 Jul 11. pii: 2168. [Epub ahead of print]11(14):

A Method for In Situ Reverse Genetic Analysis of Proteins Involved mtDNA Replication.

Natalya Kozhukhar, Domenico Spadafora, Yelitza A R Rodriguez, Mikhail F Alexeyev.

  The unavailability of tractable reverse genetic analysis approaches represents an obstacle to a better understanding of mitochondrial DNA replication. Here, we used CRISPR-Cas9 mediated gene editing to establish the conditional viability of knockouts in the key proteins involved in mtDNA replication. This observation prompted us to develop a set of tools for reverse genetic analysis in situ, which we called the GeneSwap approach. The technique was validated by identifying 730 amino acid (aa) substitutions in the mature human TFAM that are conditionally permissive for mtDNA replication. We established that HMG domains of TFAM are functionally independent, which opens opportunities for engineering chimeric TFAMs with customized properties for studies on mtDNA replication, mitochondrial transcription, and respiratory chain function. Finally, we present evidence that the HMG2 domain plays the leading role in TFAM species-specificity, thus indicating a potential pathway for TFAM-mtDNA evolutionary co-adaptations.

Keywords:  GeneSwap approach; TFAM; TFAM chimeras; TFAM knockout; TFAM-mtDNA evolutionary co-adaptation; mtDNA instability; mtDNA metabolism; mtDNA replication; mtDNA transcription

DOI:  https://doi.org/10.3390/cells11142168
Cancers (Basel). 2022 Jul 14. pii: 3432. [Epub ahead of print]14(14):

Mitochondrial Elongation and OPA1 Play Crucial Roles during the Stemness Acquisition Process in Pancreatic Ductal Adenocarcinoma.

Cristian Andres Carmona-Carmona, Elisa Dalla Pozza, Giulia Ambrosini, Barbara Cisterna, Marta Palmieri, Ilaria Decimo, José M Cuezva, Emanuela Bottani, Ilaria Dando.

  Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer with an overall 5-year survival rate of less than 9%. The high aggressiveness of PDAC is linked to the presence of a subpopulation of cancer cells with a greater tumorigenic capacity, generically called cancer stem cells (CSCs). CSCs present a heterogeneous metabolic profile that might be supported by an adaptation of mitochondrial function; however, the role of this organelle in the development and maintenance of CSCs remains controversial. To determine the role of mitochondria in CSCs over longer periods, which may reflect more accurately their quiescent state, we studied the mitochondrial physiology in CSCs at short-, medium-, and long-term culture periods. We found that CSCs show a significant increase in mitochondrial mass, more mitochondrial fusion, and higher mRNA expression of genes involved in mitochondrial biogenesis than parental cells. These changes are accompanied by a regulation of the activities of OXPHOS complexes II and IV. Furthermore, the protein OPA1, which is involved in mitochondrial dynamics, is overexpressed in CSCs and modulates the tumorsphere formation. Our findings indicate that CSCs undergo mitochondrial remodeling during the stemness acquisition process, which could be exploited as a promising therapeutic target against pancreatic CSCs.

Keywords:  OPA1; cancer stem cells; mitochondrial dynamics; mitochondrial fusion; pancreatic ductal adenocarcinoma

DOI:  https://doi.org/10.3390/cancers14143432
Int J Mol Sci. 2022 Jul 07. pii: 7553. [Epub ahead of print]23(14):

Mitochondrial Dysfunction Affects the Synovium of Patients with Rheumatoid Arthritis and Osteoarthritis Differently.

Péter Jávor, Attila Mácsai, Edina Butt, Bálint Baráth, Dávid Kurszán Jász, Tamara Horváth, Bence Baráth, Ákos Csonka, László Török, Endre Varga, Petra Hartmann.

  There is growing evidence regarding the role of mitochondrial dysfunction in osteoarthritis (OA) and rheumatoid arthritis (RA). However, quantitative comparison of synovial mitochondrial derangements in these main arthritis forms is missing. A prospective clinical study was conducted on adult patients undergoing knee surgery. Patients were allocated into RA and OA groups based on disease-specific clinical scores, while patients without arthritis served as controls. Synovial samples were subjected to high-resolution respirometry to analyze mitochondrial functions. From the total of 814 patients, 109 cases were enrolled into the study (24 RA, 47 OA, and 38 control patients) between 1 September 2019 and 31 December 2021. The decrease in complex I-linked respiration and dyscoupling of mitochondria were characteristics of RA patients, while both arthritis groups displayed reduced OxPhos activity compared to the control group. However, no significant difference was found in complex II-related activity between the OA and RA groups. The cytochrome C release and H2O2 formation were increased in both arthritis groups. Mitochondrial dysfunction was present in both arthritis groups; however, to a different extent. Consequently, mitochondrial protective agents may have major benefits for arthritis patients. Based on our current study, we recommend focusing on respiratory complex I in rheumatoid arthritis research.

Keywords:  complex I; cytochrome C; mitochondrial respiration; osteoarthritis; rheumatoid arthritis

DOI:  https://doi.org/10.3390/ijms23147553
Int J Mol Sci. 2022 Jul 13. pii: 7746. [Epub ahead of print]23(14):

Microsporidia Promote Host Mitochondrial Fragmentation by Modulating DRP1 Phosphorylation.

Jian Luo, Jinzhi Xu, Chaolu Xie, Zuoming Zhao, Junrui Guo, Yuan Wen, Tian Li, Zeyang Zhou.

  Microsporidia are obligate intracellular parasites that infect a wide variety of hosts ranging from invertebrates to vertebrates. These parasites have evolved strategies to directly hijack host mitochondria for manipulating host metabolism and immunity. However, the mechanism of microsporidia interacting with host mitochondria is unclear. In the present study, we show that microsporidian Encephalitozoon greatly induce host mitochondrial fragmentation (HMF) in multiple cells. We then reveal that the parasites promote the phosphorylation of dynamin 1-like protein (DRP1) at the 616th serine (Ser616), and dephosphorylation of the 637th serine (Ser637) by highly activating mitochondrial phosphoglycerate mutase 5 (PGAM5). These phosphorylation modifications result in the translocation of DRP1 from cytosol to the mitochondrial outer membrane, and finally lead to HMF. Furthermore, treatment with mitochondrial division inhibitor 1 (Mdivi1) significantly reduced microsporidian proliferation, indicating that the HMF are crucial for microsporidian replication. In summary, our findings reveal the mechanism that microsporidia manipulate HMF and provide references for further understanding the interactions between these ubiquitous pathogens with host mitochondria.

Keywords:  DRP1; PGAM5; host–pathogen interaction; microsporidia; mitochondrial fragmentation

DOI:  https://doi.org/10.3390/ijms23147746
Clin Psychopharmacol Neurosci. 2022 Aug 31. 20(3): 474-481

Brain Region and Sex-specific Changes in Mitochondrial Biogenesis Induced by Acute Trimethyltin Exposure.

Jung Ho Lee, Eun Hye Jang, Soon Ae Kim.

   Objective: In this study, we investigated sex- and region-specific effects of acute trimethyltin (TMT) exposure on mitochondrial biogenesis.
Methods: We treated TMT to primary neuronal cultures and 4-week-old male and female mice. We measured the mitochondrial DNA copy numbers using the quantitative polymerase chain reaction method. We also measured mitochondrial biogenesis related genes (sirtuin-1, estrogen-related receptor alpha, cytochrome C oxidase subunit IV) by western blotting.
Results: The mitochondrial DNA copy number increased in the primary hippocampal neuron; however, it decreased in the primary cortical neuron. The mitochondrial copy number increased in the hippocampus and decreased in the cortex in the TMT treated female mice, though the mitochondrial copy number increased in both cortex and hippocampus in the TMT treated male mice. TMT treatment increased sirtuin-1 expression in the male hippocampus but did not in the female brain. In the female brain, estrogen-related receptor alpha expression decreased in the cortex though there is no significant change in the male brain. The protein level of mitochondrial protein, cytochrome C oxidase subunit IV, increased in both cortex and hippocampus after TMT injection in male mice brain, but not in female mice brain.
Conclusion: Our data suggest that acute TMT exposure induces distinct sex-specific metabolic characteristics in the brain before significant sexual maturation.

Keywords:  Estrogens; Mitochondria; Sex characteristics; Trimethyltin

DOI:  https://doi.org/10.9758/cpn.2022.20.3.474
Genes (Basel). 2022 Jun 30. pii: 1182. [Epub ahead of print]13(7):

A Systematic Review of the Impact of Mitochondrial Variations on Male Infertility.

Houda Amor, Mohamad Eid Hammadeh.

  According to current estimates, infertility affects one in four couples trying to conceive. Primary or secondary infertility can be due either to both partners or only to the man or the woman. Up to 15% of infertility cases in men can be attributed to genetic factors that can lead to irreversible partial or complete spermatogenic arrest. The increased use of assisted reproductive technology (ART) has provided not only insights into the causes of male infertility but also afforded a diagnostic tool to detect and manage this condition among couples. Genes control a variety of physiological attributes, such as the hypothalamic-pituitary-gonadal axis, development, and germ cell differentiation. In the era of ART, it is important to understand the genetic basis of infertility so as to provide the most tailored therapy and counseling to couples. Genetic factors involved in male infertility can be chromosome abnormalities or single-gene disorders, mitochondrial DNA (mtDNA) mutations, Y-chromosome deletions, multifactorial disorders, imprinting disorders, or endocrine disorders of genetic origin. In this review, we discuss the role of mitochondria and the mitochondrial genome as an indicator of sperm quality and fertility.

Keywords:  male infertility; mitochondria; mtDNA

DOI:  https://doi.org/10.3390/genes13071182
Curr Biol. 2022 Jul 19. pii: S0960-9822(22)01104-6. [Epub ahead of print]

EGFR signaling activates intestinal stem cells by promoting mitochondrial biogenesis and β-oxidation.

Chenge Zhang, Yinhua Jin, Marco Marchetti, Mitchell R Lewis, Omar T Hammouda, Bruce A Edgar.

  EGFR-RAS-ERK signaling promotes growth and proliferation in many cell types, and genetic hyperactivation of RAS-ERK signaling drives many cancers. Yet, despite intensive study of upstream components in EGFR signal transduction, the identities and functions of downstream effectors in the pathway are poorly understood. In Drosophila intestinal stem cells (ISCs), the transcriptional repressor Capicua (Cic) and its targets, the ETS-type transcriptional activators Pointed (pnt) and Ets21C, are essential downstream effectors of mitogenic EGFR signaling. Here, we show that these factors promote EGFR-dependent metabolic changes that increase ISC mass, mitochondrial growth, and mitochondrial activity. Gene target analysis using RNA and DamID sequencing revealed that Pnt and Ets21C directly upregulate not only DNA replication and cell cycle genes but also genes for oxidative phosphorylation, the TCA cycle, and fatty acid beta-oxidation. Metabolite analysis substantiated these metabolic functions. The mitochondrial transcription factor B2 (mtTFB2), a direct target of Pnt, was required and partially sufficient for EGFR-driven ISC growth, mitochondrial biogenesis, and proliferation. MEK-dependent EGF signaling stimulated mitochondrial biogenesis in human RPE-1 cells, indicating the conservation of these metabolic effects. This work illustrates how EGFR signaling alters metabolism to coordinately activate cell growth and cell division.

Keywords:  Ets21C; ISC; Pointed; intestinal stem cell; mitochondrial biogenesis; mtTFB2; proliferation

DOI:  https://doi.org/10.1016/j.cub.2022.07.003
Front Pharmacol. 2022 ;13 930308

Therapeutic vs. Suprapharmacological Metformin Concentrations: Different Effects on Energy Metabolism and Mitochondrial Function in Skeletal Muscle Cells in vitro.

Kasja Pavlovic, Nina Krako Jakovljevic, Andjelka M Isakovic, Tijana Ivanovic, Ivanka Markovic, Nebojsa M Lalic.

  Metformin is an oral antidiabetic agent that has been widely used in clinical practice for over 60 years, and is currently the most prescribed antidiabetic drug worldwide. However, the molecular mechanisms of metformin action in different tissues are still not completely understood. Although metformin-induced inhibition of mitochondrial respiratory chain Complex I and activation of AMP-activated protein kinase have been observed in many studies, published data is inconsistent. Furthermore, metformin concentrations used for in vitro studies and their pharmacological relevance are a common point of debate. The aim of this study was to explore the effects of different metformin concentrations on energy metabolism and activity of relevant signaling pathways in C2C12 muscle cells in vitro. In order to determine if therapeutic metformin concentrations have an effect on skeletal muscle cells, we used micromolar metformin concentrations (50 µM), and compared the effects with those of higher, millimolar concentrations (5 mM), that have already been established to affect mitochondrial function and AMPK activity. We conducted all experiments in conditions of high (25 mM) and low glucose (5.5 mM) concentration, in order to discern the role of glucose availability on metformin action. According to our results, micromolar metformin treatment did not cause Complex I inhibition nor AMPK activation. Also, cells cultured in low glucose medium were more sensitive to Complex I inhibition, mitochondrial membrane depolarization and AMPK activation by millimolar metformin, but cells cultured in high glucose medium were more prone to induction of ROS production. In conclusion, even though suprapharmacological metformin concentrations cause Complex I inhibition and AMPK activation in skeletal muscle cells in vitro, therapeutic concentrations cause no such effect. This raises the question if these mechanisms are relevant for therapeutic effects of metformin in skeletal muscle.

Keywords:  metformin; mitochondria; respirometry; skeletal muscle; therapeutic concentration

DOI:  https://doi.org/10.3389/fphar.2022.930308
J Vis Exp. 2022 Jul 06.

Use of Bisection to Reduce Mitochondrial DNA in the Bovine Oocyte.

Laura Adams, Ying Liu, Barbara Durrant, Elena Ruggeri, Carly Young, Rebecca Krisher, Irina Polejaeva.

Interspecies somatic cell nuclear transfer (iSCNT) may be used to rescue endangered species, but two distinct populations of mitochondrial DNA (mtDNA) exist within the reconstructed embryo: one within the recipient ooplasm and one within the donor somatic cell. This mitochondrial heteroplasmy can lead to developmental issues in the embryo and the fetus. Handmade cloning protocols include oocyte bisection, which can be used to decrease the mtDNA copy number, reducing the degree of mitochondrial heteroplasmy in a reconstructed embryo. Centrifugation of denuded, mature bovine oocytes produced a visible mitochondria-dense fraction at one pole of the oocyte. Oocytes' zonae pellucidae were removed by exposure to a pronase solution. Bisection was performed using a microblade to remove the visible mitochondria fraction. qPCR was used to quantify the mtDNA present in DNA samples extracted from whole oocytes and bisected ooplasts, providing a comparison of mtDNA copy numbers before and after bisection. Copy numbers were calculated using cycle threshold values, a standard curve's regression line formula, and a ratio that included the respective sizes of mtDNA PCR products and genomic PCR products. One bovine oocyte had an average mtDNA copy number (± standard deviation) of 137,904 ± 94,768 (n = 38). One mitochondria-depleted ooplast had an average mtDNA copy number of 8,442 ± 13,806 (n = 33). Average mtDNA copies present in a mitochondria-rich ooplast were 79,390 ± 58,526 mtDNA copies (n = 28). The differences between these calculated averages indicate that the centrifugation and subsequent bisection can significantly decrease the mtDNA copy numbers present in the mitochondria-depleted ooplast when compared to the original oocyte (P < 0.0001, determined by one-way ANOVA). The reduction in mtDNA should decrease the degree of mitochondrial heteroplasmy in a reconstructed embryo, possibly fostering standard embryonic and fetal development. Supplementation with mitochondrial extract from the somatic donor cell may also be essential to achieve successful embryonic development.

DOI: https://doi.org/10.3791/64060
Sci Rep. 2022 Jul 27. 12(1): 12766

Pharmacological sequestration of mitochondrial calcium uptake protects against dementia and β-amyloid neurotoxicity.

Elena F Shevtsova, Plamena R Angelova, Olga A Stelmashchuk, Noemi Esteras, Nataliia A Vasil'eva, Andrey V Maltsev, Pavel N Shevtsov, Alexander V Shaposhnikov, Vladimir P Fisenko, Sergey O Bachurin, Andrey Y Abramov.

All forms of dementia including Alzheimer's disease are currently incurable. Mitochondrial dysfunction and calcium alterations are shown to be involved in the mechanism of neurodegeneration in Alzheimer's disease. Previously we have described the ability of compound Tg-2112x to protect neurons via sequestration of mitochondrial calcium uptake and we suggest that it can also be protective against neurodegeneration and development of dementia. Using primary co-culture neurons and astrocytes we studied the effect of Tg-2112x and its derivative Tg-2113x on β-amyloid-induced changes in calcium signal, mitochondrial membrane potential, mitochondrial calcium, and cell death. We have found that both compounds had no effect on β-amyloid or acetylcholine-induced calcium changes in the cytosol although Tg2113x, but not Tg2112x reduced glutamate-induced calcium signal. Both compounds were able to reduce mitochondrial calcium uptake and protected cells against β-amyloid-induced mitochondrial depolarization and cell death. Behavioral effects of Tg-2113x on learning and memory in fear conditioning were also studied in 3 mouse models of neurodegeneration: aged (16-month-old) C57Bl/6j mice, scopolamine-induced amnesia (3-month-old mice), and 9-month-old 5xFAD mice. It was found that Tg-2113x prevented age-, scopolamine- and cerebral amyloidosis-induced decrease in fear conditioning. In addition, Tg-2113x restored fear extinction of aged mice. Thus, reduction of the mitochondrial calcium uptake protects neurons and astrocytes against β-amyloid-induced cell death and contributes to protection against dementia of different ethology. These compounds could be used as background for the developing of a novel generation of disease-modifying neuroprotective agents.

DOI: https://doi.org/10.1038/s41598-022-16817-9
Cell Rep. 2022 Jul 26. pii: S2211-1247(22)00907-X. [Epub ahead of print]40(4): 111105

Skeletal progenitors preserve proliferation and self-renewal upon inhibition of mitochondrial respiration by rerouting the TCA cycle.

Guillaume Tournaire, Shauni Loopmans, Steve Stegen, Gianmarco Rinaldi, Guy Eelen, Sophie Torrekens, Karen Moermans, Peter Carmeliet, Bart Ghesquière, Bernard Thienpont, Sarah-Maria Fendt, Nick van Gastel, Geert Carmeliet.

  A functional electron transport chain (ETC) is crucial for supporting bioenergetics and biosynthesis. Accordingly, ETC inhibition decreases proliferation in cancer cells but does not seem to impair stem cell proliferation. However, it remains unclear how stem cells metabolically adapt. In this study, we show that pharmacological inhibition of complex III of the ETC in skeletal stem and progenitor cells induces glycolysis side pathways and reroutes the tricarboxylic acid (TCA) cycle to regenerate NAD+ and preserve cell proliferation. These metabolic changes also culminate in increased succinate and 2-hydroxyglutarate levels that inhibit Ten-eleven translocation (TET) DNA demethylase activity, thereby preserving self-renewal and multilineage potential. Mechanistically, mitochondrial malate dehydrogenase and reverse succinate dehydrogenase activity proved to be essential for the metabolic rewiring in response to ETC inhibition. Together, these data show that the metabolic plasticity of skeletal stem and progenitor cells allows them to bypass ETC blockade and preserve their self-renewal.

Keywords:  CP: Metabolism; CP: Stem cell research; NAD regeneration; TCA rerouting; TET activity; cell-based regenerative medicine; electron transport chain; metabolic plasticity; proliferation; reverse succinate dehydrogenase; self-renewal; skeletal stem cells

DOI:  https://doi.org/10.1016/j.celrep.2022.111105
Physiol Rep. 2022 Jul;10(14): e15369

Severe COVID-19 correlates with lower mitochondrial cristae density in PBMCs and greater sitting time in humans.

Mauricio Castro-Sepulveda, German Tapia, Mauro Tuñón-Suárez, Alejandra Diaz, Hugo Marambio, Mayalen Valero-Breton, Rodrigo Fernández-Verdejo, Hermann Zbinden-Foncea.

  An interaction between mitochondrial dynamics, physical activity levels, and COVID-19 severity has been previously hypothesized. However, this has not been tested. We aimed to compare mitochondrial morphology and cristae density of PBMCs between subjects with non-severe COVID-19, subjects with severe COVID-19, and healthy controls. Additionally, we compared the level of moderate-vigorous physical activity (MVPA) and sitting time between groups. Blood samples were taken to obtain PBMCs. Mitochondrial dynamics were assessed by electron microscopy images and western blot of protein that regulate mitochondrial dynamics. The International Physical Activity Questionnaire (IPAQ; short version) was used to estimate the level of MVPA and the sitting time The patients who develop severe COVID-19 (COVID-19++) not present alterations of mitochondrial size neither mitochondrial density in comparison to non-severe patients COVID-19 (COVID-19) and control subjects (CTRL). However, compared to CTRL, COVID-19 and COVID-19++ groups have lower mitochondrial cristae length, a higher proportion of abnormal mitochondrial cristae. The COVID-19++ group has lower number (trend) and length of mitochondrial cristae in comparison to COVID-19 group. COVID-19, but not COVID-19++ group had lower Opa 1, Mfn 2 and SDHB (Complex II) proteins than CTRL group. Besides, COVID-19++ group has a higher time sitting. Our results show that low mitochondrial cristae density, potentially due to physical inactivity, is associated with COVID-19 severity.

Keywords:  COVID-19; PBMCs; SARS-CoV-2; metabolism; mitochondrial dynamics; mitochondrial fusion

DOI:  https://doi.org/10.14814/phy2.15369
Cells. 2022 Jul 14. pii: 2203. [Epub ahead of print]11(14):

Differential Susceptibility of Retinal Neurons to the Loss of Mitochondrial Biogenesis Factor Nrf1.

Takae Kiyama, Ching-Kang Chen, Annie Zhang, Chai-An Mao.

  The retina, the accessible part of the central nervous system, has served as a model system to study the relationship between energy utilization and metabolite supply. When the metabolite supply cannot match the energy demand, retinal neurons are at risk of death. As the powerhouse of eukaryotic cells, mitochondria play a pivotal role in generating ATP, produce precursors for macromolecules, maintain the redox homeostasis, and function as waste management centers for various types of metabolic intermediates. Mitochondrial dysfunction has been implicated in the pathologies of a number of degenerative retinal diseases. It is well known that photoreceptors are particularly vulnerable to mutations affecting mitochondrial function due to their high energy demand and susceptibility to oxidative stress. However, it is unclear how defective mitochondria affect other retinal neurons. Nuclear respiratory factor 1 (Nrf1) is the major transcriptional regulator of mitochondrial biogenesis, and loss of Nrf1 leads to defective mitochondria biogenesis and eventually cell death. Here, we investigated how different retinal neurons respond to the loss of Nrf1. We provide in vivo evidence that the disruption of Nrf1-mediated mitochondrial biogenesis results in a slow, progressive degeneration of all retinal cell types examined, although they present different sensitivity to the deletion of Nrf1, which implicates differential energy demand and utilization, as well as tolerance to mitochondria defects in different neuronal cells. Furthermore, transcriptome analysis on rod-specific Nrf1 deletion uncovered a previously unknown role of Nrf1 in maintaining genome stability.

Keywords:  Nrf1; RNA-seq; bipolar cells; ganglion cells; mitochondrial biogenesis; photoreceptor degeneration; retina disease; transcriptome

DOI:  https://doi.org/10.3390/cells11142203
Autophagy. 2022 Jul 27. 1-26

TNK2/ACK1-mediated phosphorylation of ATP5F1A (ATP synthase F1 subunit alpha) selectively augments survival of prostate cancer while engendering mitochondrial vulnerability.

Surbhi Chouhan, Mithila Sawant, Cody Weimholt, Jingqin Luo, Robert W Sprung, Mailyn Terrado, David M Mueller, H Shelton Earp, Nupam P Mahajan.

  The challenge of rapid macromolecular synthesis enforces the energy-hungry cancer cell mitochondria to switch their metabolic phenotypes, accomplished by activation of oncogenic tyrosine kinases. Precisely how kinase activity is directly exploited by cancer cell mitochondria to meet high-energy demand, remains to be deciphered. Here we show that a non-receptor tyrosine kinase, TNK2/ACK1 (tyrosine kinase non receptor 2), phosphorylated ATP5F1A (ATP synthase F1 subunit alpha) at Tyr243 and Tyr246 (Tyr200 and 203 in the mature protein, respectively) that not only increased the stability of complex V, but also increased mitochondrial energy output in cancer cells. Further, phospho-ATP5F1A (p-Y-ATP5F1A) prevented its binding to its physiological inhibitor, ATP5IF1 (ATP synthase inhibitory factor subunit 1), causing sustained mitochondrial activity to promote cancer cell growth. TNK2 inhibitor, (R)-9b reversed this process and induced mitophagy-based autophagy to mitigate prostate tumor growth while sparing normal prostate cells. Further, depletion of p-Y-ATP5F1A was needed for (R)-9b-mediated mitophagic response and tumor growth. Moreover, Tnk2 transgenic mice displayed increased p-Y-ATP5F1A and loss of mitophagy and exhibited formation of prostatic intraepithelial neoplasia (PINs). Consistent with these data, a marked increase in p-Y-ATP5F1A was seen as prostate cancer progressed to the malignant stage. Overall, this study uncovered the molecular intricacy of tyrosine kinase-mediated mitochondrial energy regulation as a distinct cancer cell mitochondrial vulnerability and provided evidence that TNK2 inhibitors can act as "mitocans" to induce cancer-specific mitophagy.AbbreviationsATP5F1A: ATP synthase F1 subunit alpha; ATP5IF1: ATP synthase inhibitory factor subunit 1; CRPC: castration-resistant prostate cancer; DNM1L: dynamin 1 like; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; Mdivi-1: mitochondrial division inhibitor 1; Mut-ATP5F1A: Y243,246A mutant of ATP5F1A; OXPHOS: oxidative phosphorylation; PC: prostate cancer; PINK1: PTEN induced kinase 1; p-Y-ATP5F1A: phosphorylated tyrosine 243 and 246 on ATP5F1A; TNK2/ACK1: tyrosine kinase non receptor 2; Ub: ubiquitin; WT: wild type.

Keywords:  ATP5F1A; ATP5IF1; TNK2/ACK1; mitochondrial dysfunction; mitochondrial vulnerability; mitophagy; tyrosine phosphorylation

DOI:  https://doi.org/10.1080/15548627.2022.2103961
Clin Sci (Lond). 2022 Jul 29. 136(14): 1081-1110

Targeting skeletal muscle mitochondrial health in obesity.

Chantal A Pileggi, Breana G Hooks, Ruth McPherson, Robert R M Dent, Mary-Ellen Harper.

  Metabolic demands of skeletal muscle are substantial and are characterized normally as highly flexible and with a large dynamic range. Skeletal muscle composition (e.g., fiber type and mitochondrial content) and metabolism (e.g., capacity to switch between fatty acid and glucose substrates) are altered in obesity, with some changes proceeding and some following the development of the disease. Nonetheless, there are marked interindividual differences in skeletal muscle composition and metabolism in obesity, some of which have been associated with obesity risk and weight loss capacity. In this review, we discuss related molecular mechanisms and how current and novel treatment strategies may enhance weight loss capacity, particularly in diet-resistant obesity.

Keywords:  metabolic disorders; metabolic regulation; mitochondria; oxidative phosphorylation; skeletal muscle

DOI:  https://doi.org/10.1042/CS20210506
Antioxidants (Basel). 2022 Jul 22. pii: 1421. [Epub ahead of print]11(8):

Oxidative Stress in Tauopathies: From Cause to Therapy.

Fernando Bartolome, Eva Carro, Carolina Alquezar.

  Oxidative stress (OS) is the result of an imbalance between the production of reactive oxygen species (ROS) and the antioxidant capacity of cells. Due to its high oxygen demand, the human brain is highly susceptible to OS and, thus, it is not a surprise that OS has emerged as an essential component of the pathophysiology of several neurodegenerative diseases, including tauopathies. Tauopathies are a heterogeneous group of age-related neurodegenerative disorders characterized by the deposition of abnormal tau protein in the affected neurons. With the worldwide population aging, the prevalence of tauopathies is increasing, but effective therapies have not yet been developed. Since OS seems to play a key role in tauopathies, it has been proposed that the use of antioxidants might be beneficial for tau-related neurodegenerative diseases. Although antioxidant therapies looked promising in preclinical studies performed in cellular and animal models, the antioxidant clinical trials performed in tauopathy patients have been disappointing. To develop effective antioxidant therapies, the molecular mechanisms underlying OS in tauopathies should be completely understood. Here, we review the link between OS and tauopathies, emphasizing the causes of OS in these diseases and the role of OS in tau pathogenesis. We also summarize the antioxidant therapies proposed as a potential treatment for tauopathies and discuss why they have not been completely translated to clinical trials. This review aims to provide an integrated perspective of the role of OS and antioxidant therapies in tauopathies. In doing so, we hope to enable a more comprehensive understanding of OS in tauopathies that will positively impact future studies.

Keywords:  antioxidants; oxidative stress; tau; tauopathies

DOI:  https://doi.org/10.3390/antiox11081421
J Clin Med. 2022 Jul 20. pii: 4209. [Epub ahead of print]11(14):

Primary and Secondary Mitochondrial Diseases: Etiologies and Therapeutic Strategies.

Daniela Valenti, Rosa Anna Vacca.

Mitochondria are complex and multifaceted organelles that constitute a dynamic network of signaling platforms playing a pivotal role in cellular energy-generating processes [...].

DOI: https://doi.org/10.3390/jcm11144209
Free Radic Biol Med. 2022 Jul 21. pii: S0891-5849(22)00483-X. [Epub ahead of print]

Evidence of impaired mitochondrial cellular bioenergetics in ocular fibroblasts derived from glaucoma patients.

Neeru A Vallabh, Jane Armstrong, Gabriela Czanner, Brian Mc Donagh, Anshoo Choudhary, David N Criddle, Colin E Willoughby.

  Glaucoma is a progressive optic neuropathy characterized by the neurodegeneration of the retinal ganglion cells (RGCs) resulting in irreversible visual impairment and eventual blindness. RGCs are extremely susceptible to mitochondrial compromise due to their marked bioenergetic requirements and morphology. There is increasing interest in therapies targeting mitochondrial health as a method of preventing visual loss in managing glaucoma. The bioenergetic profile of Tenon's ocular fibroblasts from glaucoma patients and controls was investigated using the Seahorse XF24 analyser. Impaired mitochondrial cellular bioenergetics was detected in glaucomatous ocular fibroblasts including basal respiration, maximal respiration and spare capacity. Spare respiratory capacity levels reflect mitochondrial bio-energetic adaptability in response to pathophysiological stress. Basal oxidative stress was elevated in glaucomatous Tenon's ocular fibroblasts and hydrogen peroxide (H2O2) induced reactive oxygen species (ROS) simulated the glaucomatous condition in normal Tenon's ocular fibroblasts. This work supports the role of therapeutic interventions to target oxidative stress or provide mitochondrial energetic support in glaucoma.

Keywords:  Bioenergetics; Glaucoma; Mitochondria; Oxidative stress; Seahorse XF analyser; Tenon's fibroblast

DOI:  https://doi.org/10.1016/j.freeradbiomed.2022.07.009
Structure. 2022 Jul 12. pii: S0969-2126(22)00269-6. [Epub ahead of print]

Catalytic cycling of human mitochondrial Lon protease.

Inayathulla Mohammed, Kai A Schmitz, Niko Schenck, Dimitrios Balasopoulos, Annika Topitsch, Timm Maier, Jan Pieter Abrahams.

  The mitochondrial Lon protease (LonP1) regulates mitochondrial health by removing redundant proteins from the mitochondrial matrix. We determined LonP1 in eight nucleotide-dependent conformational states by cryoelectron microscopy (cryo-EM). The flexible assembly of N-terminal domains had 3-fold symmetry, and its orientation depended on the conformational state. We show that a conserved structural motif around T803 with a high similarity to the trypsin catalytic triad is essential for proteolysis. We show that LonP1 is not regulated by redox potential, despite the presence of two conserved cysteines at disulfide-bonding distance in its unfoldase core. Our data indicate how sequential ATP hydrolysis controls substrate protein translocation in a 6-fold binding change mechanism. Substrate protein translocation, rather than ATP hydrolysis, is a rate-limiting step, suggesting that LonP1 is a Brownian ratchet with ATP hydrolysis preventing translocation reversal. 3-fold rocking motions of the flexible N-domain assembly may assist thermal unfolding of the substrate protein.

Keywords:  AAA+ protein; chaperone; molecular motor; proteolysis

DOI:  https://doi.org/10.1016/j.str.2022.06.006
Metabolites. 2022 Jul 09. pii: 630. [Epub ahead of print]12(7):

NAD+ Precursors: A Questionable Redundancy.

Carles Canto.

  The last decade has seen a strong proliferation of therapeutic strategies for the treatment of metabolic and age-related diseases based on increasing cellular NAD+ bioavailability. Among them, the dietary supplementation with NAD+ precursors-classically known as vitamin B3-has received most of the attention. Multiple molecules can act as NAD+ precursors through independent biosynthetic routes. Interestingly, eukaryote organisms have conserved a remarkable ability to utilize all of these different molecules, even if some of them are scarcely found in nature. Here, we discuss the possibility that the conservation of all of these biosynthetic pathways through evolution occurred because the different NAD+ precursors might serve specialized purposes.

Keywords:  NAD+; niacin; nicotinamide riboside; vitamin B3

DOI:  https://doi.org/10.3390/metabo12070630
Biomolecules. 2022 Jul 21. pii: 1008. [Epub ahead of print]12(7):

Mitochondria Transfer from Adipose Stem Cells Improves the Developmental Potential of Cryopreserved Oocytes.

Udayanga Sanath Kankanam Gamage, Shu Hashimoto, Yuki Miyamoto, Tatsuya Nakano, Masaya Yamanaka, Akiko Koike, Manabu Satoh, Yoshiharu Morimoto.

  Although it is not a well-established technology, oocyte cryopreservation is becoming prevalent in assisted reproductive technologies in response to the growing demands of patients' sociological and pathological conditions. Oocyte cryopreservation can adversely affect the developmental potential of oocytes by causing an increase in intracellular oxidative stresses and damage to the mitochondrial structure. In this study, we studied whether autologous adipose stem cell (ASC) mitochondria supplementation with vitrified and warmed oocytes could restore post-fertilization development that decreased due to mitochondrial damage following cryopreservation. ASC mitochondria showed similar morphology to oocytes' mitochondria and had a higher ATP production capacity. The vitrified-warmed oocytes from juvenile mice were supplemented with ASC mitochondria at the same time as intracellular sperm injection (ICSI), after which we compared their developmental capacity and the mitochondria quality of 2-cell embryos. We found that, compared to their counterpart, mitochondria supplementation significantly improved development from 2-cell embryos to blastocysts (56.8% vs. 38.2%) and ATP production in 2-cell embryos (905.6 & 561.1 pmol), while reactive oxygen species levels were comparable. With these results, we propose that ASC mitochondria supplementation could restore the quality of cryopreserved oocytes and enhance the embryo developmental capacity, signifying another possible approach for mitochondrial transplantation therapy.

Keywords:  adipose stem cell; embryo development; mitochondria supplementation; oocyte cryopreservation

DOI:  https://doi.org/10.3390/biom12071008
Antioxidants (Basel). 2022 Jul 18. pii: 1389. [Epub ahead of print]11(7):

In Vitro Efficacy and Molecular Mechanism of Curcumin Analog in Pathological Regulation of Spinocerebellar Ataxia Type 3.

Yu-Ling Wu, Jui-Chih Chang, Yi-Chun Chao, Hardy Chan, Mingli Hsieh, Chin-San Liu.

  Unlike other nuclear factor erythroid-2-related factor 2 (Nrf2) activators, the mechanism of action of curcumin analog, ASC-JM17 (JM17), in regulating oxidative homeostasis remains unknown. Spinocerebellar ataxia type 3 (SCA3) is an inherited polyglutamine neurodegenerative disease caused mainly by polyglutamine neurotoxicity and oxidative stress. Presently, we compared actions of JM17 with those of known Nrf2 activators, omaveloxolone (RTA-408) and dimethyl fumarate (DMF), using human neuroblastoma SK-N-SH cells with stable transfection of full-length ataxin-3 protein with 78 CAG repeats (MJD78) to clarify the resulting pathological mechanism by assaying mitochondrial function, mutant ataxin-3 protein toxicity, and oxidative stress. JM17, 1 μM, comprehensively restored mitochondrial function, decreased mutant protein aggregates, and attenuated intracellular/mitochondrial reactive oxygen species (ROS) levels. Although JM17 induced dose-dependent Nrf2 activation, a low dose of JM17 (less than 5 μM) still had a better antioxidant ability compared to the other Nrf2 activators and specifically increased mitochondrial superoxide dismutase 2 in an Nrf2-dependent manner as shown by knockdown experiments with siRNA. It showed that activation of Nrf2 in response to ROS generated in mitochondria could play an import role in the benefit of JM17. This study presents the diversified regulation of JM17 in a pathological process and helped develop more effective therapeutic strategies for SCA3.

Keywords:  anti-oxidative enzymes; curcumin analog; mitochondrial function; nuclear factor erythroid-2 related factor 2; spinocerebellar ataxia type 3

DOI:  https://doi.org/10.3390/antiox11071389
Mitochondrion. 2022 Jul 26. pii: S1567-7249(22)00069-1. [Epub ahead of print]

Epigenetic control of mitochondrial fission enables hepatic stellate cells activation in liver fibrosis via PGC-1α-Drp1 pathway.

Jing-Jing Yang, Juan Wang, Yang Yang, Feng Sun, Yan Yang, Jun Li, Hui Tao, Chao Lu.

  Although excessive mitochondrial fission is linked to cell activation, its significance in hepatic stellate cells (HSCs) activation and liver fibrosis is unknown. Here we show that excessive mitochondrial fission triggers HSCs activation and liver fibrosis degradation by the epigenetic regulation. We used a combination of in vitro and in vivo models, including HSCs and clinical cases or CCl4-induced liver fibrosis mice, was performed to investigate the regulation and function of mitochondrial fission in HSCs activation and liver fibrosis. Herein, we show that DNMT3A and Drp1 is up regulated in fibrosis livers and mice liver fibrosis tissues, while PGC-1α was decreased. Interestingly, down expression of DNMT3A substantially reduced Drp1 levels, collagen accumulation, and interstitial fibrosis, while significantly increased PGC-1α levels. Furthermore, silencing DNMT3A remarkably inhibits HSCs activation and mitochondrial fission both in vivo and in vitro. Mechanistically, co-immunoprecipitation analysis revealed that DNMT3A bound to pull down the protein of PGC-1α. These findings indicated that epigenetic control of mitochondrial fission enables HSCs activation in liver fibrosis via PGC-1α-Drp1 pathway, and provide new insight into the relationship between mitochondrial fission and liver fibrosis.

Keywords:  Activation; DNMT3A; Drp1; Hepatic stellate cells; Liver fibrosis; Mitochondrial fission

DOI:  https://doi.org/10.1016/j.mito.2022.07.005