bims-mitmed 2023-02-05 papers

bims-mitmed

Biomed News

on Mitochondrial medicine

Issue of 2023‒02‒05
twenty-two papers selected by
Dario Brunetti
Fondazione IRCCS Istituto Neurologico

An explanation of how mutant and wild-type mitochondria might stably co-exist in inherited mitochondrial diseases.
De novo frameshift variant in MT-ND1 causes a mitochondrial complex I deficiency associated with MELAS syndrome.
Metabolic function of autophagy is essential for cell survival.
Mitochondrial protein import machinery conveys stress signals to the cytosol and beyond.
Adult skeletal muscle PRC is involved in maintaining mitochondrial content.
A mouse model of human mitofusin 2-related lipodystrophy exhibits adipose-specific mitochondrial stress and reduced leptin secretion.
Intra-cellular to inter-organ mitochondrial communication in striated muscle in health and disease.
Genome-wide characterization of mitochondrial DNA methylation in human brain.
Sigma-1 receptor maintains ATAD3A as a monomer to inhibit mitochondrial fragmentation at the mitochondria-associated membrane in amyotrophic lateral sclerosis.
Neuronal activity-driven O-GlcNAcylation promotes mitochondrial plasticity.
A single dose of exercise stimulates skeletal muscle mitochondrial plasticity in myotonic dystrophy type 1.
IP3 receptor trafficking at the ER-mitochondria contacts impacts on mitochondrial Ca2+ homeostasis and metabolism.
Metformin induces mitochondrial fission and reduces energy metabolism by targeting respiratory chain complex I in hepatic stellate cells to reverse liver fibrosis.
A case report: New-onset refractory status epilepticus in a patient with FASTKD2-related mitochondrial disease.
Membrane-domain mutations in respiratory complex I impede catalysis but do not uncouple proton pumping from ubiquinone reduction.
Mitochondrial dysfunction in human hypertrophic cardiomyopathy is linked to cardiomyocyte architecture disruption and corrected by improving NADH-driven mitochondrial respiration.
Peroxisome proliferator-activated receptor (PPAR) agonists as a potential therapy for inherited metabolic disorders.
Mitochondrial transplantation ameliorates hippocampal damage following status epilepticus.
Mitochondrial citrate metabolism and efflux regulates trophoblast differentiation.
Irisin exhibits neuroprotection by preventing mitochondrial damage in Parkinson's disease.
Does supplementation of oocytes with additional mtDNA influence developmental outcome?
MitoQuicLy: a high-throughput method for quantifying cell-free DNA from human plasma, serum, and saliva.

PNAS Nexus. 2022 Sep;1(4): pgac192

An explanation of how mutant and wild-type mitochondria might stably co-exist in inherited mitochondrial diseases.

Axel Kowald, Felix P Kemeth, Tom B L Kirkwood.

  Mitochondria are cellular organelles of crucial relevance for the survival of metazoan organisms. Damage to the mitochondrial DNA can give rise to a variety of mitochondrial diseases and is thought also to be involved in the aging process. The fate of mtDNA mutants is controlled by their synthesis as well as degradation and mathematical models can help to better understand this complex interplay. We present here a model that combines a replicative advantage for mtDNA mutants with selective degradation enabled by mitochondrial fission and fusion processes. The model not only shows that the cell has efficient means to deal with (many) types of mutants but, surprisingly, also predicts that under certain conditions a stable co-existence of mutant and wild-type mtDNAs is possible. We discuss how this new finding might explain how mitochondria can be at the heart of processes with such different phenotypes as mitochondrial diseases and aging.

Keywords:  aging; mathematical model; mitochondrial disease

DOI:  https://doi.org/10.1093/pnasnexus/pgac192
Gene. 2023 Jan 27. pii: S0378-1119(23)00070-7. [Epub ahead of print] 147229

De novo frameshift variant in MT-ND1 causes a mitochondrial complex I deficiency associated with MELAS syndrome.

Xiaoting Lou, Yuwei Zhou, Zhimei Liu, Yaojun Xie, Luyi Zhang, Suzhou Zhao, Shuai Gong, Xiuwei Zhuo, Junling Wang, Lifang Dai, Xiaotun Ren, Xiao Tong, Liangliang Jiang, Hezhi Fang, Fang Fang, Jianxin Lyu.

  BACKGROUND: The variant m.3571_3572insC/MT-ND1 thus far only reported in oncocytic tumors of different tissues. However, the role of m.3571_3572insC in inherited mitochondrial diseases has yet to be elucidated.METHODS: A patient diagnosed with MELAS syndrome was recruited, and detailed medical records were collected and reviewed. The muscle was biopsied for mitochondrial respiratory chain enzyme activity. Series of fibroblast clones bearing different m.3571_3572insC variant loads were generated from patient-derived fibroblasts and subjected to functional assays.
RESULTS: Complex I deficiency was confirmed in the patient's muscle via mitochondrial respiratory chain enzyme activity assay. The m.3571_3572insC was filtered for the candidate variant of the patient according to the guidelines for mitochondrial mRNA variants interpretation. Three cell clones with different m.3571_3572insC variant loads were generated to evaluate mitochondrial function. Blue native PAGE analysis revealed that m.3571_3572insC caused a deficiency in the mitochondrial complex I. Oxygen consumption rate, ATP production, and lactate assays found an impairment of cellular bioenergetic capacity due to m.3571_3572insC. Mitochondrial membrane potential was decreased, and mitochondrial reactive oxygen species production was increased with the variant of m.3571_3572insC. According to the competitive cell growth assay, the mutant cells had impaired cell growth capacity compared to wild type.
CONCLUSIONS: A novel variant m.3571_3572insC was identified in a patient diagnosed with MELAS syndrome, and the variant impaired mitochondrial respiration by decreasing the activity of complex I. In conclusion, the genetic spectrum of mitochondrial diseases was expanded by including m.3571_3572insC/MT-ND1.

Keywords:  Heteroplasmic; MELAS syndrome; MT-ND1; de novo; m.3571_3572insC

DOI:  https://doi.org/10.1016/j.gene.2023.147229
Autophagy. 2023 Feb 01. 1-3

Metabolic function of autophagy is essential for cell survival.

Lucia Sedlackova, Tetsushi Kataura, Sovan Sarkar, Viktor I Korolchuk.

  Age-related human pathologies present with a multitude of molecular and metabolic phenotypes, which individually or synergistically contribute to tissue degeneration. However, current lack of understanding of the interdependence of these molecular pathologies limits the potential range of existing therapeutic intervention strategies. In our study, we set out to understand the chain of molecular events, which underlie the loss of cellular viability in macroautophagy/autophagy deficiency associated with aging and age-related disease. We discover a novel axis linking autophagy, a cellular waste disposal pathway, and a metabolite, nicotinamide adenine dinucleotide (NAD). The axis connects multiple organelles, molecules and stress response pathways mediating cellular demise when autophagy becomes dysfunctional. By elucidating the steps on the path from efficient mitochondrial recycling to NAD maintenance and ultimately cell viability, we highlight targets potentially receptive to therapeutic interventions in a range of genetic and age-related diseases associated with autophagy dysfunction.Abbreviations: IMM: inner mitochondrial membrane; NAD: nicotinamide dinucleotide; OXPHOS: oxidative phosphorylation; PARP: poly(ADP-ribose) polymerase; ROS: reactive oxygen species.

Keywords:  Aging; DNA damage; NAD; PARP; ROS; autophagy; mitochondria; mitophagy; sirtuins

DOI:  https://doi.org/10.1080/15548627.2023.2165753
Bioessays. 2023 Jan 29. e2200160

Mitochondrial protein import machinery conveys stress signals to the cytosol and beyond.

Eirini Lionaki, Ilias Gkikas, Nektarios Tavernarakis.

  Mitochondria hold diverse and pivotal roles in fundamental processes that govern cell survival, differentiation, and death, in addition to organismal growth, maintenance, and aging. The mitochondrial protein import system is a major contributor to mitochondrial biogenesis and lies at the crossroads between mitochondrial and cellular homeostasis. Recent findings highlight the mitochondrial protein import system as a signaling hub, receiving inputs from other cellular compartments and adjusting its function accordingly. Impairment of protein import, in a physiological, or disease context, elicits adaptive responses inside and outside mitochondria. In this review, we discuss recent developments, relevant to the mechanisms of mitochondrial protein import regulation, with a particular focus on quality control, proteostatic and metabolic cellular responses, triggered upon impairment of mitochondrial protein import.

Keywords:  metabolism; mitochondrial protein import; mitochondrial unfolded protein response; mitophagy; proteostasis

DOI:  https://doi.org/10.1002/bies.202200160
Am J Physiol Regul Integr Comp Physiol. 2023 Jan 30.

Adult skeletal muscle PRC is involved in maintaining mitochondrial content.

Drue Benefield, Yazeed Abdelmageed, Jahmel Fowler, Serenah Smith, Kassandra Arias-Parbul, Courtney Dunning, Glenn C Rowe.

  The peroxisome proliferator-activated receptor gamma coactivator-1 (PGC-1) family of transcriptional coactivators are regulators of mitochondrial oxidative capacity and content in skeletal muscle. Many of these conclusions are based primarily on gain-of-function studies using muscle-specific overexpression of PGC1s. We have previously reported that genetic deletion of both PGC-1α and PGC-1β in adult skeletal muscle resulted in a significant reduction in oxidative capacity with no effect on mitochondrial content. However, the contribution of PGC-1-related coactivator (PRC), the third PGC-1 family member, in regulating skeletal muscle mitochondria is unknown. Therefore, we generated an inducible skeletal muscle-specific PRC knockout mouse (iMS-PRC-KO) to assess the contribution of PRC in skeletal muscle mitochondrial function. We measured mRNA expression of electron transport chain (ETC) subunits as well as markers of mitochondrial content in the iMS-PRC-KO animals and observed an increase in ETC gene expression and mitochondrial content. Furthermore, the increase in ETC gene expression and mitochondrial content was associated with increased expression of PGC-1α and PGC-1β. We therefore generated an adult inducible PGC-1 knockout mouse in which all PGC-1 family members are deleted (iMS-PGC-1TKO). The iMS-PGC-1TKO animals exhibited a reduction in ETC mRNA expression and mitochondrial content. These data suggest that in the absence of PRC alone, compensation occurs by increasing PGC-1α and PGC-1β to maintain mitochondrial content. Moreover, removal of all three PGC-1s in skeletal muscle result in a reduction in both ETC mRNA expression and mitochondrial content. Taken together, these results suggests that PRC plays a role in maintaining baseline mitochondrial content in skeletal muscle.

Keywords:  PRC; mitochondria; mitochondrial biogenesis; skeletal muscle

DOI:  https://doi.org/10.1152/ajpregu.00241.2022
Elife. 2023 Feb 01. pii: e82283. [Epub ahead of print]12

A mouse model of human mitofusin 2-related lipodystrophy exhibits adipose-specific mitochondrial stress and reduced leptin secretion.

Jake P Mann, Xiaowen Duan, Satish Patel, Luis Carlos Tábara, Fabio Scurria, Anna Alvarez-Guaita, Afreen Haider, Ineke Luijten, Matthew Page, Margherita Protasoni, Koini Lim, Sam Virtue, Stephen O'Rahilly, Martin Armstrong, Julien Prudent, Robert K Semple, David B Savage.

  Mitochondrial dysfunction has been reported in obesity and insulin resistance, but primary genetic mitochondrial dysfunction is generally not associated with these, arguing against a straightforward causal relationship. A rare exception, recently identified in humans, is a syndrome of lower body adipose loss, leptin-deficient severe upper body adipose overgrowth, and insulin resistance caused by the p.Arg707Trp mutation in MFN2, encoding mitofusin 2. How the resulting selective form of mitochondrial dysfunction leads to tissue- and adipose depot-specific growth abnormalities and systemic biochemical perturbation is unknown. To address this, Mfn2R707W/R707W knock-in mice were generated and phenotyped on chow and high fat diets. Electron microscopy revealed adipose-specific mitochondrial morphological abnormalities. Oxidative phosphorylation measured in isolated mitochondria was unperturbed, but the cellular integrated stress response was activated in adipose tissue. Fat mass and distribution, body weight, and systemic glucose and lipid metabolism were unchanged, however serum leptin and adiponectin concentrations, and their secretion from adipose explants were reduced. Pharmacological induction of the integrated stress response in wild-type adipocytes also reduced secretion of leptin and adiponectin, suggesting an explanation for the in vivo findings. These data suggest that the p.Arg707Trp MFN2 mutation selectively perturbs mitochondrial morphology and activates the integrated stress response in adipose tissue. In mice, this does not disrupt most adipocyte functions or systemic metabolism, whereas in humans it is associated with pathological adipose remodelling and metabolic disease. In both species, disproportionate effects on leptin secretion may relate to cell autonomous induction of the integrated stress response.

Keywords:  cell biology; mouse

DOI:  https://doi.org/10.7554/eLife.82283
Endocr Rev. 2023 Feb 02. pii: bnad004. [Epub ahead of print]

Intra-cellular to inter-organ mitochondrial communication in striated muscle in health and disease.

Neoma T Boardman, Giulia Trani, Marco Scalabrin, Vanina Romanello, Rob C I Wüst.

  Mitochondria both sense biochemical and energetic input in addition to communicating signals regarding the energetic state of the cell. Increasingly, these signaling organelles are key for regulating different cell functions. This review summarizes recent advances in mitochondrial communication in striated muscle, with specific focus on the processes by which mitochondria communicate with each other, other organelles and across distant organ systems. Inter-mitochondrial communication in striated muscle is mediated via conduction of the mitochondrial membrane potential to adjacent mitochondria, physical interactions, mitochondrial fusion or fission and via nannotunnels, allowing for the exchange of proteins, mitochondrial DNA, nucleotides, and peptides. Within striated muscle cells, mitochondria-organelle communication can modulate overall cell function. The various mechanisms in which mitochondria communicate mitochondrial fitness to the rest of the body suggest that extracellular mitochondrial signaling is key during health and disease. Whereas mitochondrial-derived vesicles might excrete mitochondrial-derived endocrine compounds, stimulation of mitochondrial stress can lead to the release of fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15) into the circulation to modulate whole-body physiology. Circulating mitochondrial DNA are well-known alarmins that trigger the immune system and may help to explain low-grade inflammation in various chronic diseases. Impaired mitochondrial function and communication are central in common heart and skeletal muscle pathologies, including cardiomyopathies, insulin resistance, and sarcopenia. Lastly, important new advances in research in mitochondrial endocrinology, communication, medical horizons and translational aspects are discussed.

Keywords:  FGF21; GDF15; mitochondria-organelle interactions; mitochondrial cristae; mitochondrial dynamics; myokines; respiratory supercomplexes

DOI:  https://doi.org/10.1210/endrev/bnad004
Front Endocrinol (Lausanne). 2022 ;13 1059120

Genome-wide characterization of mitochondrial DNA methylation in human brain.

Matthew Devall, Darren M Soanes, Adam R Smith, Emma L Dempster, Rebecca G Smith, Joe Burrage, Artemis Iatrou, Eilis Hannon, Claire Troakes, Karen Moore, Paul O'Neill, Safa Al-Sarraj, Leonard Schalkwyk, Jonathan Mill, Michael Weedon, Katie Lunnon.

  Background: There is growing interest in the role of DNA methylation in regulating the transcription of mitochondrial genes, particularly in brain disorders characterized by mitochondrial dysfunction. Here, we present a novel approach to interrogate the mitochondrial DNA methylome at single base resolution using targeted bisulfite sequencing. We applied this method to investigate mitochondrial DNA methylation patterns in post-mortem superior temporal gyrus and cerebellum brain tissue from seven human donors.Results: We show that mitochondrial DNA methylation patterns are relatively low but conserved, with peaks in DNA methylation at several sites, such as within the D-LOOP and the genes MT-ND2, MT-ATP6, MT-ND4, MT-ND5 and MT-ND6, predominantly in a non-CpG context. The elevated DNA methylation we observe in the D-LOOP we validate using pyrosequencing. We identify loci that show differential DNA methylation patterns associated with age, sex and brain region. Finally, we replicate previously reported differentially methylated regions between brain regions from a methylated DNA immunoprecipitation sequencing study.
Conclusions: We have annotated patterns of DNA methylation at single base resolution across the mitochondrial genome in human brain samples. Looking to the future this approach could be utilized to investigate the role of mitochondrial epigenetic mechanisms in disorders that display mitochondrial dysfunction.

Keywords:  5-Methylcytosine (5mC); Brain; DNA Methylation; Mitochondria; epigenetics; mtDNA

DOI:  https://doi.org/10.3389/fendo.2022.1059120
Neurobiol Dis. 2023 Feb 01. pii: S0969-9961(23)00045-1. [Epub ahead of print] 106031

Sigma-1 receptor maintains ATAD3A as a monomer to inhibit mitochondrial fragmentation at the mitochondria-associated membrane in amyotrophic lateral sclerosis.

Seiji Watanabe, Mai Horiuchi, Yuri Murata, Okiru Komine, Noe Kawade, Akira Sobue, Koji Yamanaka.

  Organelle contact sites are multifunctional platforms for maintaining cellular homeostasis. Alternations of the mitochondria-associated membranes (MAM), one of the organelle contact sites where the endoplasmic reticulum (ER) is tethered to the mitochondria, have been involved in the pathogenesis of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). However, the detailed mechanisms through which MAM integrity is disrupted in ALS have not been fully elucidated. Here, we examined whether AAA ATPase domain-containing protein 3A (ATAD3A), a mitochondrial membrane AAA ATPase accumulating at the MAM, is involved in ALS. We found that sigma-1 receptor (σ1R), an ER-resident MAM protein causative for inherited juvenile ALS, required ATAD3A to maintain the MAM. In addition, σ1R retained ATAD3A as a monomer, which is associated with an inhibition of mitochondrial fragmentation. ATAD3A dimerization and mitochondrial fragmentation were significantly induced in σ1R-deficient or SOD1-linked ALS mouse spinal cords. Overall, these observations indicate that MAM induction by σ1R depends on ATAD3A and that σ1R maintains ATAD3A as a monomer to inhibit mitochondrial fragmentation. Our findings suggest that targeting σ1R-ATAD3A axis would be promising for a novel therapeutic strategy to treat mitochondrial dysfunction in neurological disorders, including ALS.

Keywords:  ATPase domain-containing; Lateral sclerosis; Mitochondria-associated membrane/sigma-1; Protein 3A/amyotrophic; Receptor/AAA

DOI:  https://doi.org/10.1016/j.nbd.2023.106031
bioRxiv. 2023 Jan 11. pii: 2023.01.11.523512. [Epub ahead of print]

Neuronal activity-driven O-GlcNAcylation promotes mitochondrial plasticity.

Seungyoon B Yu, Richard G Sanchez, Zachary D Papich, Thomas C Whisenant, Majid Ghassemian, John N Koberstein, Melissa L Stewart, Gulcin Pekkurnaz.

Neuronal activity is an energy-intensive process that is largely sustained by instantaneous fuel utilization and ATP synthesis. However, how neurons couple ATP synthesis rate to fuel availability is largely unknown. Here, we demonstrate that the metabolic sensor enzyme O-GlcNAc transferase regulates neuronal activity-driven mitochondrial bioenergetics. We show that neuronal activity upregulates O-GlcNAcylation mainly in mitochondria. Mitochondrial O-GlcNAcylation is promoted by activity-driven fuel consumption, which allows neurons to compensate for high energy expenditure based on fuel availability. To determine the proteins that are responsible for these adjustments, we mapped the mitochondrial O-GlcNAcome of neurons. Finally, we determine that neurons fail to meet activity-driven metabolic demand when O-GlcNAcylation dynamics are prevented. Our findings suggest that O-GlcNAcylation provides a fuel-dependent feedforward control mechanism in neurons to optimize mitochondrial performance based on neuronal activity. This mechanism thereby couples neuronal metabolism to mitochondrial bioenergetics and plays a key role in sustaining energy homeostasis.

DOI: https://doi.org/10.1101/2023.01.11.523512
Acta Physiol (Oxf). 2023 Feb 01. e13943

A single dose of exercise stimulates skeletal muscle mitochondrial plasticity in myotonic dystrophy type 1.

Andrew I Mikhail, Alexander Manta, Sean Y Ng, Aislin K Osborne, Stephanie R Mattina, Mark R Mackie, Vladimir Ljubicic.

  AIM: Myotonic dystrophy type 1 (DM1) is the second most common muscular dystrophy after Duchenne and is the most prevalent muscular dystrophy in adults. DM1 patients that participate in aerobic exercise training experience several physiological benefits concomitant with improved muscle mitochondrial function without alterations in typical DM1-specific disease mechanisms, which suggests that correcting organelle health is key to ameliorate the DM1 pathology. However, our understanding of the molecular mechanisms of mitochondrial turnover and dynamics in DM1 skeletal muscle is lacking.METHODS: Skeletal muscle tissue were sampled from healthy and DM1 mice under sedentary conditions and at several recovery time-points following an exhaustive treadmill run.
RESULTS: We demonstrate that DM1 patients exhibit an imbalance in the transcriptional apparatus for mitochondrial turnover and dynamics in skeletal muscle. Additionally, DM1 mice displayed elevated expression of autophagy and mitophagy regulators. A single dose of exercise successfully enhanced canonical exercise molecular pathways and skeletal muscle mitochondrial biogenesis despite failing to alter the cellular pathology in DM1 mice. However, treadmill running stimulated coordinated organelle fusion and fission signaling, as well as improved alternative splicing of Optic atrophy 1. Exercise also evoked autophagy and mitophagy pathways in DM1 skeletal muscle resulting in the normalized expression of autophagy- and lysosome-related machinery responsible for the clearance of dysfunctional organelles.
CONCLUSION: Collectively, our data indicate that mitochondrial dynamics and turnover processes in DM1 skeletal muscle are initiated with a single dose of exercise, which may underlie the adaptive benefits previously documented in DM1 mice and patients.

Keywords:  AMP-activated protein kinase; autophagy; biogenesis; dynamics; mitophagy

DOI:  https://doi.org/10.1111/apha.13943
Cell Calcium. 2023 Jan 25. pii: S0143-4160(23)00012-X. [Epub ahead of print]110 102700

IP3 receptor trafficking at the ER-mitochondria contacts impacts on mitochondrial Ca2+ homeostasis and metabolism.

Karim Rahhali, Fabio Di Lisa, Nina Kaludercic.

  The close contacts between endoplasmic reticulum and mitochondria (ERMCs) play a key role in metabolic regulation, Ca2+ homeostasis, reactive oxygen species production, and many other cell functions. Nevertheless, it is not fully clear how these contacts dynamically rearrange to support cell functions. In a recent Nature Communications article [1], Katona et al. elegantly showed that motile IP3Rs can be captured at ERMCs to promptly mediate Ca2+ transfer and stimulate mitochondrial oxidative metabolism.

Keywords:  Contact sites; Endoplasmic reticulum; IP(3) receptor; Mitochondria

DOI:  https://doi.org/10.1016/j.ceca.2023.102700
Int J Biochem Cell Biol. 2023 Jan 27. pii: S1357-2725(23)00014-6. [Epub ahead of print] 106375

Metformin induces mitochondrial fission and reduces energy metabolism by targeting respiratory chain complex I in hepatic stellate cells to reverse liver fibrosis.

Ying Su, Chenjian Hou, Meili Wang, Kehan Ren, Danmei Zhou, Xiaoli Liu, Shanyu Zhao, Xiuping Liu.

  The activation and proliferation of hepatic stellate cells (HSCs) are critical processes for the treatment of liver fibrosis. It is necessary to identify effective drugs for the treatment of liver fibrosis and elucidate their mechanisms of action. Metformin can inhibit HSCs; however, no systematic studies demonstrating the effects of metformin on mitochondria in HSCs have been reported. This study demonstrated that metformin induces mitochondrial fission by phosphorylating AMPK/DRP1 (S616) in HSCs to decrease the expression of α-SMA and collagen. Additionally, metformin repressed the total ATP production rate, especially the production rate of ATP produced through mitochondrial oxidative phosphorylation, by inhibiting the enzymatic activity of complex I. Further analysis revealed that metformin strongly constrained the transcription of mitochondrial genes (ND1-ND6 and ND4L) that encode the core subunits of respiratory chain I. Upregulation of the mRNA expression of HK2 and GLUT1 slightly enhanced glycolysis. Additionally, metformin increased mitochondrial DNA (mtDNA) copy number to suppress the proliferation and activation of HSCs, indicating that mtDNA copy number can alter the fate of HSCs. In conclusion, metformin can induce mitochondrial fragmentation and low-level energy metabolism in HSCs, thereby suppressing HSCs activation and proliferation to reverse liver fibrosis.

Keywords:  Hepatic stellate cells (HSCs); Liver fibrosis; Metformin; Mitochondrial dynamics; oxidative phosphorylation

DOI:  https://doi.org/10.1016/j.biocel.2023.106375
Front Neurol. 2022 ;13 1063733

A case report: New-onset refractory status epilepticus in a patient with FASTKD2-related mitochondrial disease.

Alexandra Astner-Rohracher, Matthias Mauritz, Markus Leitinger, Fabio Rossini, Gudrun Kalss, Caroline Neuray, Elisabeth Retter, Saskia B Wortmann, Melanie T Achleitner, Johannes A Mayr, Eugen Trinka.

  Objectives: New-onset refractory status epilepticus (NORSE) is associated with high morbidity and mortality. Despite extensive work-up, the underlying etiology remains unknown in 50% of affected individuals. Mitochondrial disorders represent rare causes of NORSE. Biallelic variants in FASTKD2 were reported as a cause of infantile encephalomyopathy with refractory epilepsy.Case description: In the study, we report a previously healthy 14-year-old with a new, homozygous FASTKD2 variant presenting with NORSE. Following a seizure-free period of 7 years, he experienced another super-refractory SE and subsequently developed drug-resistant focal epilepsy, mild myopathy, optic atrophy, and discrete psychomotor slowing. Structural MRI at the time of NORSE showed right temporo-parieto-occipital FLAIR hyperintensity and diffusion restriction, with extensive right hemispheric atrophy at the age of 22 years. Whole-exome sequencing revealed a novel homozygous loss of function variant [c.(1072C>T);(1072C>T)] [p.(Arg358Ter);(Arg358Ter)] in FASTKD2 (NM_001136193), resulting in a premature termination codon in the protein-coding region and loss of function of FASTKD2. Oxidative phosphorylation (OXPHOS) in muscle and skin fibroblasts was unremarkable.
Conclusion: This is the first case of a normally developed adolescent with a new homozygous loss of function variant in FASTKD2, manifesting with NORSE. The phenotypical spectrum of FASTKD2-related mitochondrial disease is heterogeneous, ranging from recurrent status epilepticus and refractory focal epilepsy in an adolescent with normal cognitive development to severe forms of infantile mitochondrial encephalopathy. Although mitochondrial diseases are rare causes of NORSE, clinical features such as young age at onset and multi-system involvement should trigger genetic testing. Early diagnosis is essential for counseling and treatment considerations.

Keywords:  FASTKD2 mutation; drug-resistant epilepsy; genetic epilepsies; mitochondrial disease; new-onset refractory status epilepticus (NORSE)

DOI:  https://doi.org/10.3389/fneur.2022.1063733
PNAS Nexus. 2022 Nov;1(5): pgac276

Membrane-domain mutations in respiratory complex I impede catalysis but do not uncouple proton pumping from ubiquinone reduction.

Owen D Jarman, Judy Hirst.

  Respiratory complex I [NADH:ubiquinone (UQ) oxidoreductase] captures the free energy released from NADH oxidation and UQ reduction to pump four protons across an energy-transducing membrane and power ATP synthesis. Mechanisms for long-range energy coupling in complex I have been proposed from structural data but not yet evaluated by robust biophysical and biochemical analyses. Here, we use the powerful bacterial model system Paracoccus denitrificans to investigate 14 mutations of key residues in the membrane-domain Nqo13/ND4 subunit, defining the rates and reversibility of catalysis and the number of protons pumped per NADH oxidized. We reveal new insights into the roles of highly conserved charged residues in lateral energy transduction, confirm the purely structural role of the Nqo12/ND5 transverse helix, and evaluate a proposed hydrated channel for proton uptake. Importantly, even when catalysis is compromised the enzyme remains strictly coupled (four protons are pumped per NADH oxidized), providing no evidence for escape cycles that circumvent blocked proton-pumping steps.

Keywords:  NADH:ubiquinone oxidoreductase; biological energy transduction; electron transport chain; proton pumping; respiratory chain

DOI:  https://doi.org/10.1093/pnasnexus/pgac276
Eur Heart J. 2023 Feb 03. pii: ehad028. [Epub ahead of print]

Mitochondrial dysfunction in human hypertrophic cardiomyopathy is linked to cardiomyocyte architecture disruption and corrected by improving NADH-driven mitochondrial respiration.

Edgar E Nollet, Inez Duursma, Anastasiya Rozenbaum, Moritz Eggelbusch, Rob C I Wüst, Stephan A C Schoonvelde, Michelle Michels, Mark Jansen, Nicole N van der Wel, Kenneth C Bedi, Kenneth B Margulies, Jeff Nirschl, Diederik W D Kuster, Jolanda van der Velden.

  AIMS: Genetic hypertrophic cardiomyopathy (HCM) is caused by mutations in sarcomere protein-encoding genes (i.e. genotype-positive HCM). In an increasing number of patients, HCM occurs in the absence of a mutation (i.e. genotype-negative HCM). Mitochondrial dysfunction is thought to be a key driver of pathological remodelling in HCM. Reports of mitochondrial respiratory function and specific disease-modifying treatment options in patients with HCM are scarce.METHODS AND RESULTS: Respirometry was performed on septal myectomy tissue from patients with HCM (n = 59) to evaluate oxidative phosphorylation and fatty acid oxidation. Mitochondrial dysfunction was most notably reflected by impaired NADH-linked respiration. In genotype-negative patients, but not genotype-positive patients, NADH-linked respiration was markedly depressed in patients with an indexed septal thickness ≥10 compared with <10. Mitochondrial dysfunction was not explained by reduced abundance or fragmentation of mitochondria, as evaluated by transmission electron microscopy. Rather, improper organization of mitochondria relative to myofibrils (expressed as a percentage of disorganized mitochondria) was strongly associated with mitochondrial dysfunction. Pre-incubation with the cardiolipin-stabilizing drug elamipretide and raising mitochondrial NAD+ levels both boosted NADH-linked respiration.
CONCLUSION: Mitochondrial dysfunction is explained by cardiomyocyte architecture disruption and is linked to septal hypertrophy in genotype-negative HCM. Despite severe myocardial remodelling mitochondria were responsive to treatments aimed at restoring respiratory function, eliciting the mitochondria as a drug target to prevent and ameliorate cardiac disease in HCM. Mitochondria-targeting therapy may particularly benefit genotype-negative patients with HCM, given the tight link between mitochondrial impairment and septal thickening in this subpopulation.

Keywords:  Cardiomyocyte architecture; Hypertrophic cardiomyopathy; Metabolism; Mitochondrial dysfunction; Mitochondrial therapy

DOI:  https://doi.org/10.1093/eurheartj/ehad028
Biochem Pharmacol. 2023 Jan 26. pii: S0006-2952(23)00024-2. [Epub ahead of print] 115433

Peroxisome proliferator-activated receptor (PPAR) agonists as a potential therapy for inherited metabolic disorders.

Bianca Seminotti, Mateus Grings, Nícolas Manzke Glänzel, Jerry Vockley, Guilhian Leipnitz.

  Inherited metabolic disorders (IMDs) are genetic disorders that cause a disruption of a specific metabolic pathway leading to biochemical, clinical and pathophysiological sequelae. While the metabolite abnormalities in body fluids and tissues can usually be defined by directed or broad-spectrum metabolomic analysis, the pathophysiology of these changes is often not obvious. Mounting evidence has revealed that secondary mitochondrial dysfunction, mainly oxidative phosphorylation impairment and elevated reactive oxygen species, plays a pivotal role in many disorders. Peroxisomal proliferator-activated receptors (PPARs) consist of a group of nuclear hormone receptors (PPARα, PPARβ/δ, and PPARγ) that regulate multiple cellular functions and processes, including response to oxidative stress, inflammation, lipid metabolism, and mitochondrial bioenergetics and biogenesis. In this context, the activation of PPARs has been shown to stimulate oxidative phosphorylation and reduce reactive species levels. Thus, pharmacological treatment with PPAR activators, such as fibrates, has gained much attention in the last 15 years. This review summarizes preclinical (animal models and patient-derived cells) and clinical data on the effect of PPARs in IMDs.

Keywords:  Inherited metabolic disorders; bezafibrate; mitochondrial dysfunction; peroxisome proliferator-activated receptors-PPAR

DOI:  https://doi.org/10.1016/j.bcp.2023.115433
Animal Model Exp Med. 2023 Feb 03.

Mitochondrial transplantation ameliorates hippocampal damage following status epilepticus.

Xiaoxia Jia, Qinghua Wang, Jianlun Ji, Wenchun Lu, Zhidong Liu, Hao Tian, Lin Guo, Yun Wang.

  BACKGROUND: Hippocampal damage caused by status epilepticus (SE) can bring about cognitive decline and emotional disorders, which are common clinical comorbidities in patients with epilepsy. It is therefore imperative to develop a novel therapeutic strategy for protecting hippocampal damage after SE. Mitochondrial dysfunction is one of contributing factors in epilepsy. Given the therapeutic benefits of mitochondrial replenishment by exogenous mitochondria, we hypothesized that transplantation of mitochondria would be capable of ameliorating hippocampal damage following SE.METHODS: Pilocarpine was used to induced SE in mice. SE-generated cognitive decline and emotional disorders were determined using novel object recognition, the tail suspension test, and the open field test. SE-induced hippocampal pathology was assessed by quantifying loss of neurons and activation of microglia and astrocytes. The metabolites underlying mitochondrial transplantation were determined using metabonomics.
RESULTS: The results showed that peripheral administration of isolated mitochondria could improve cognitive deficits and depressive and anxiety-like behaviors. Exogenous mitochondria blunted the production of reactive oxygen species, proliferation of microglia and astrocytes, and loss of neurons in the hippocampus. The metabonomic profiles showed that mitochondrial transplantation altered multiple metabolic pathways such as sphingolipid signaling pathway and carbon metabolism. Among potential affected metabolites, mitochondrial transplantation decreased levels of sphingolipid (d18:1/18:0) and methylmalonic acid, and elevated levels of D-fructose-1,6-bisphosphate.
CONCLUSION: To the best of our knowledge, these findings provide the first direct experimental evidence that artificial mitochondrial transplantation is capable of ameliorating hippocampal damage following SE. These new findings support mitochondrial transplantation as a promising therapeutic strategy for epilepsy-associated psychiatric and cognitive disorders.

Keywords:  cognitive deficit; emotional disorders; hippocampal damage; mitochondrial transplantation; status epilepticus

DOI:  https://doi.org/10.1002/ame2.12310
bioRxiv. 2023 Jan 22. pii: 2023.01.22.525071. [Epub ahead of print]

Mitochondrial citrate metabolism and efflux regulates trophoblast differentiation.

Renee M Mahr, Snehalata Jena, Sereen K Nashif, Alisa B Nelson, Adam J Rauckhorst, Ferrol I Rome, Ryan D Sheldon, Curtis C Hughey, Patrycja Puchalska, Micah D Gearhart, Eric B Taylor, Peter A Crawford, Sarah A Wernimont.

Cytotrophoblasts fuse to form and renew syncytiotrophoblasts necessary to maintain placental health throughout gestation. During cytotrophoblast to syncytiotrophoblast differentiation, cells undergo regulated metabolic and transcriptional reprogramming. Mitochondria play a critical role in differentiation events in cellular systems, thus we hypothesized that mitochondrial metabolism played a central role in trophoblast differentiation. In this work, we employed static and stable isotope tracing untargeted metabolomics methods along with gene expression and histone acetylation studies in an established cell culture model of trophoblast differentiation. Trophoblast differentiation was associated with increased abundance of the TCA cycle intermediates citrate and α-ketoglutarate. Citrate was preferentially exported from mitochondria in the undifferentiated state but was retained to a larger extent within mitochondria upon differentiation. Correspondingly, differentiation was associated with decreased expression of the mitochondrial citrate transporter (CIC). CRISPR/Cas9 disruption of the mitochondrial citrate carrier showed that CIC is required for biochemical differentiation of trophoblasts. Loss of CIC resulted in broad alterations in gene expression and histone acetylation. These gene expression changes were partially rescued through acetate supplementation. Taken together, these results highlight a central role for mitochondrial citrate metabolism in orchestrating histone acetylation and gene expression during trophoblast differentiation.

DOI: https://doi.org/10.1101/2023.01.22.525071
NPJ Parkinsons Dis. 2023 Jan 31. 9(1): 13

Irisin exhibits neuroprotection by preventing mitochondrial damage in Parkinson's disease.

Xi Zhang, Sutong Xu, Yong Hu, Qiulu Liu, Chenming Liu, Huazhen Chai, Yuping Luo, Lingjing Jin, Siguang Li.

Exercise has been proposed as an effective non-pharmacological management for Parkinson's disease (PD) patients. Irisin, a recently identified myokine, is increased by exercise and plays pivotal roles in energy metabolism. However, it remains unknown whether irisin has any protective effects on PD. Here, we found that serum irisin levels of PD patients were markedly elevated after 12-week regular exercise, which had a positive correlation with improved balance function scored by Berg Balance Scale. Treatment with exogenous irisin could improve motor function, and reduce dopaminergic neurodegeneration in PD models. Meanwhile, irisin could reduce cell apoptosis by renovating mitochondrial function in PD models, which was reflected in decreased oxidative stress, increased mitochondrial complex I activity and mitochondrial content, increased mitochondrial biogenesis, and repaired mitochondrial morphology. Furthermore, irisin regulated the aforementioned aspects by upregulating downstream Akt signaling pathway and ERK1/2 signaling pathway through integrin receptors rather than directly targeting mitochondria. With the use of small-molecule inhibitors, it was found that irisin can reduce apoptosis, restore normal mitochondrial biogenesis, and improve mitochondrial morphology and dynamic balance in PD models by activating Akt signaling pathway and ERK1/2 signaling pathway. And irisin reduced oxidative stress via activating ERK1/2 signaling pathway. The results revealed that exogenous irisin conferred neuroprotection relieving apoptosis and oxidative stress, restraining mitochondrial fragmentation, and promoting mitochondrial respiration and biogenesis in PD models, and irisin exerted the aforementioned effects by activating Akt signaling pathway and ERK1/2 signaling pathway. Thus, peripherally delivered irisin might be a promising candidate for therapeutic targeting of PD.

DOI: https://doi.org/10.1038/s41531-023-00453-9
iScience. 2023 Feb 17. 26(2): 105956

Does supplementation of oocytes with additional mtDNA influence developmental outcome?

Stephen McIlfatrick, Sean O'Leary, Takashi Okada, Alexander Penn, Vy Hoang Thao Nguyen, Lisa McKenny, Shang-Yu Huang, Eryk Andreas, John Finnie, Roy Kirkwood, Justin C St John.

  Introducing extra mitochondrial DNA (mtDNA) into oocytes at fertilization can rescue poor quality oocytes. However, supplementation alters DNA methylation and gene expression profiles of preimplantation embryos. To determine if these alterations impacted offspring, we introduced mtDNA from failed-to-mature sister (autologous) or third party (heterologous) oocytes into mature oocytes and transferred zygotes into surrogates. Founders exhibited significantly greater daily weight gain (heterologous) and growth rates (heterologous and autologous) to controls. In weaners, cholesterol, bilirubin (heterologous and autologous), anion gap, and lymphocyte count (autologous) were elevated. In mature pigs, potassium (heterologous) and bicarbonate (autologous) were altered. mtDNA and imprinted gene analyses did not reveal aberrant profiles. Neither group exhibited gross anatomical, morphological, or histopathological differences that would lead to clinically significant lesions. Female founders were fertile and their offspring exhibited modified weight and height gain, biochemical, and hematological profiles. mtDNA supplementation induced minor differences that did not affect health and well-being.

Keywords:  Developmental biology; Porcine reproduction; Reproductive medicine

DOI:  https://doi.org/10.1016/j.isci.2023.105956
bioRxiv. 2023 Jan 04. pii: 2023.01.04.522744. [Epub ahead of print]

MitoQuicLy: a high-throughput method for quantifying cell-free DNA from human plasma, serum, and saliva.

Jeremy Michelson, Shannon Rausser, Amanda Peng, Temmie Yu, Gabriel Sturm, Caroline Trumpff, Brett A Kaufman, Alex J Rai, Martin Picard.

Circulating cell-free mitochondrial DNA (cf-mtDNA) is an emerging biomarker of psychobiological stress and disease which predicts mortality and is associated with various disease states. To evaluate the contribution of cf-mtDNA to health and disease states, standardized high-throughput procedures are needed to quantify cf-mtDNA in relevant biofluids. Here, we describe MitoQuicLy: Mito chondrial DNA Qu antification in c ell-free samples by Ly sis. We demonstrate high agreement between MitoQuicLy and the commonly used column-based method, although MitoQuicLy is faster, cheaper, and requires a smaller input sample volume. Using 10 µL of input volume with MitoQuicLy, we quantify cf-mtDNA levels from three commonly used plasma tube types, two serum tube types, and saliva. We detect, as expected, significant inter-individual differences in cf-mtDNA across different biofluids. However, cf-mtDNA levels between concurrently collected plasma, serum, and saliva from the same individual differ on average by up to two orders of magnitude and are poorly correlated with one another, pointing to different cf-mtDNA biology or regulation between commonly used biofluids in clinical and research settings. Moreover, in a small sample of healthy women and men (n=34), we show that blood and saliva cf-mtDNAs correlate with clinical biomarkers differently depending on the sample used. The biological divergences revealed between biofluids, together with the lysis-based, cost-effective, and scalable MitoQuicLy protocol for biofluid cf-mtDNA quantification, provide a foundation to examine the biological origin and significance of cf-mtDNA to human health.

DOI: https://doi.org/10.1101/2023.01.04.522744