bims-mitdis 2023-09-17 papers

bims-mitdis

Biomed News

on Mitochondrial disorders

Issue of 2023‒09‒17
forty papers selected by
Catalina Vasilescu, Helmholz Munich

Outer mitochondrial membrane E3 Ub ligase MARCH5 controls mitochondrial steps in peroxisome biogenesis.
Alternative to lysosomal degradation: mitochondrial removal via EVs.
Prefoldin 2 contributes to mitochondrial morphology and function.
Molecular pathway of mitochondrial preprotein import through the TOM-TIM23 supercomplex.
Mitochondrial degradation: Mitophagy and beyond.
Early steps in the biogenesis of mitochondrially encoded oxidative phosphorylation subunits.
PKR activation in mitochondrial unfolded protein response-mitochondrial dsRNA might do the trick.
Mit.OnOff: A Science Communication Project for Public Awareness about Mitochondrial Cytopathies.
Novel pathogenic UQCRC2 variants in a female with normal neurodevelopment.
Elevated susceptibility to exogenous seizure triggers and impaired interneuron excitability in a mouse model of Leigh syndrome epilepsy.
RatioCRISPR: A ratiometric biochip based on CRISPR/Cas12a for automated and multiplexed detection of heteroplasmic SNPs in mitochondrial DNA.
Bilateral and Symmetrical Basal Ganglia Calcifications May Aid in Mitochondrial Disease Diagnosis in Resource-Limited Settings.
Cold-stimulated brown adipose tissue activation is related to changes in serum metabolites relevant to NAD+ metabolism in humans.
A nucleotide diphosphate kinase mediates tethering between mitochondria prior to fusion.
Mitochondrial GTP metabolism controls reproductive aging in C. elegans.
Mitochondrial membrane potential acts as a retrograde signal to regulate cell cycle progression.
Using light to drive energy transduction in metazoan aging.
Mitochondrial Cardiomyopathy Due to the MT-TI Variant m.4300A>G Requires Comprehensive Clinical and Genetic Workup.
Successful transcatheter mitral valve repair for functional mitral regurgitation in a patient with mitochondrial cardiomyopathy: a case report.
Comparative multi-omics analyses of cardiac mitochondrial stress in three mouse models of frataxin deficiency.
Global analysis of aging-related protein structural changes uncovers enzyme-polymerization-based control of longevity.
Trazodone rescues dysregulated synaptic and mitochondrial nascent proteomes in prion neurodegeneration.
Nrf2 depletion in the context of loss-of-function Keap1 leads to mitolysosome accumulation.
Dynamic lipidome alterations associated with human health, disease and ageing.
Remdesivir increases mtDNA copy number causing mild alterations to oxidative phosphorylation.
Complex regulatory processes control exercise adaptations of skeletal muscle.
Reversible cardiac function and left ventricular hypertrophy in a Chinese man with mitochondrial myopathy: a case report.
Cardiolipin prolongs the lifetimes of respiratory proteins in Drosophila flight muscle.
Mitochondrial dysfunction in neurodegenerative disorders: Potential therapeutic application of mitochondrial transfer to central nervous system-residing cells.
A systematic comparison of human mitochondrial genome assembly tools.
Atlas of primary cell-type-specific sequence models of gene expression and variant effects.
Fasting and non-fasting plasma levels of monomethyl branched chain fatty acids: Implications for maple syrup urine disease.
Partial Skeletal Muscle-Specific Drp1 Knockout Enhances Insulin Sensitivity in Diet-Induced Obese Mice, But Not in Lean Mice.
Parkinson's iPSC trial.
The Parkinson's disease-associated mutation LRRK2 G2385R alters mitochondrial biogenesis via the PGC-1α-TFAM pathway.
Discovery of a First-in-Class CD38 Inhibitor for the Treatment of Mitochondrial Myopathy.
Clinical Trial Highlights: Modulators of Mitochondrial Function.
NRF2 signaling in cytoprotection and metabolism.
MMD collaborates with ACSL4 and MBOAT7 to promote polyunsaturated phosphatidylinositol remodeling and susceptibility to ferroptosis.
Clustering-predicted structures at the scale of the known protein universe.

bioRxiv. 2023 Sep 01. pii: 2023.08.31.555756. [Epub ahead of print]

Outer mitochondrial membrane E3 Ub ligase MARCH5 controls mitochondrial steps in peroxisome biogenesis.

Nicolas Verhoeven, Yumiko Oshima, Etienne Cartier, Albert Neutzner, Liron Boyman, Mariusz Karbowski.

Peroxisome de novo biogenesis requires yet unidentified mitochondrial proteins. We report that the outer mitochondrial membrane (OMM)-associated E3 Ub ligase MARCH5 is vital for generating mitochondria-derived pre-peroxisomes. MARCH5 knockout results in accumulation of immature peroxisomes and lower expression of various peroxisomal proteins. Upon fatty acid-induced peroxisomal biogenesis, MARCH5 redistributes to newly formed peroxisomes; the peroxisomal biogenesis under these conditions is inhibited in MARCH5 knockout cells. MARCH5 activity-deficient mutants are stalled on peroxisomes and induce accumulation of peroxisomes containing high levels of the OMM protein Tom20 (mitochondria-derived pre-peroxisomes). Furthermore, depletion of peroxisome biogenesis factor Pex14 leads to the formation of MARCH5- and Tom20-positive peroxisomes, while no peroxisomes are detected in Pex14/MARCH5 dko cells. Reexpression of WT, but not MARCH5 mutants, restores Tom20-positive pre-peroxisomes in Pex14/MARCH5 dko cells. Thus, MARCH5 acts upstream of Pex14 in mitochondrial steps of peroxisome biogenesis. Our data validate the hybrid, mitochondria-dependent model of peroxisome biogenesis and reveal that MARCH5 is an essential mitochondrial protein in this process.Summary: The authors found that mitochondrial E3 Ub ligase MARCH5 controls the formation of mitochondria-derived pre-peroxisomes. The data support the hybrid, mitochondria-dependent model of peroxisome biogenesis and reveal that MARCH5 is an essential mitochondrial protein in this process.

DOI: https://doi.org/10.1101/2023.08.31.555756
Nat Rev Mol Cell Biol. 2023 Sep 11.

Alternative to lysosomal degradation: mitochondrial removal via EVs.

Paulina Strzyz.

DOI: https://doi.org/10.1038/s41580-023-00660-5
BMC Biol. 2023 09 12. 21(1): 193

Prefoldin 2 contributes to mitochondrial morphology and function.

Ismail Tahmaz, Somayeh Shahmoradi Ghahe, Monika Stasiak, Kamila P Liput, Katarzyna Jonak, Ulrike Topf.

  BACKGROUND: Prefoldin is an evolutionarily conserved co-chaperone of the tailless complex polypeptide 1 ring complex (TRiC)/chaperonin containing tailless complex 1 (CCT). The prefoldin complex consists of six subunits that are known to transfer newly produced cytoskeletal proteins to TRiC/CCT for folding polypeptides. Prefoldin function was recently linked to the maintenance of protein homeostasis, suggesting a more general function of the co-chaperone during cellular stress conditions. Prefoldin acts in an adenosine triphosphate (ATP)-independent manner, making it a suitable candidate to operate during stress conditions, such as mitochondrial dysfunction. Mitochondrial function depends on the production of mitochondrial proteins in the cytosol. Mechanisms that sustain cytosolic protein homeostasis are vital for the quality control of proteins destined for the organelle and such mechanisms among others include chaperones.RESULTS: We analyzed consequences of the loss of prefoldin subunits on the cell proliferation and survival of Saccharomyces cerevisiae upon exposure to various cellular stress conditions. We found that prefoldin subunits support cell growth under heat stress. Moreover, prefoldin facilitates the growth of cells under respiratory growth conditions. We showed that mitochondrial morphology and abundance of some respiratory chain complexes was supported by the prefoldin 2 (Pfd2/Gim4) subunit. We also found that Pfd2 interacts with Tom70, a receptor of mitochondrial precursor proteins that are targeted into mitochondria.
CONCLUSIONS: Our findings link the cytosolic prefoldin complex to mitochondrial function. Loss of the prefoldin complex subunit Pfd2 results in adaptive cellular responses on the proteome level under physiological conditions suggesting a continuous need of Pfd2 for maintenance of cellular homeostasis. Within this framework, Pfd2 might support mitochondrial function directly as part of the cytosolic quality control system of mitochondrial proteins or indirectly as a component of the protein homeostasis network.

Keywords:  Chaperone; Mitochondria; Pfd2/Gim4; Prefoldin; Proteostasis; Tom70

DOI:  https://doi.org/10.1186/s12915-023-01695-y
Nat Struct Mol Biol. 2023 Sep 11.

Molecular pathway of mitochondrial preprotein import through the TOM-TIM23 supercomplex.

Xueyin Zhou, Yuqi Yang, Guopeng Wang, Shanshan Wang, Dongjie Sun, Xiaomin Ou, Yuke Lian, Long Li.

Over half of mitochondrial proteins are imported from the cytosol via the pre-sequence pathway, controlled by the TOM complex in the outer membrane and the TIM23 complex in the inner membrane. The mechanisms through which proteins are translocated via the TOM and TIM23 complexes remain unclear. Here we report the assembly of the active TOM-TIM23 supercomplex of Saccharomyces cerevisiae with translocating polypeptide substrates. Electron cryo-microscopy analyses reveal that the polypeptide substrates pass the TOM complex through the center of a Tom40 subunit, interacting with a glutamine-rich region. Structural and biochemical analyses show that the TIM23 complex contains a heterotrimer of the subunits Tim23, Tim17 and Mgr2. The polypeptide substrates are shielded from lipids by Mgr2 and Tim17, which creates a translocation pathway characterized by a negatively charged entrance and a central hydrophobic region. These findings reveal an unexpected pre-sequence pathway through the TOM-TIM23 supercomplex spanning the double membranes of mitochondria.

DOI: https://doi.org/10.1038/s41594-023-01103-7
Mol Cell. 2023 Sep 07. pii: S1097-2765(23)00656-1. [Epub ahead of print]

Mitochondrial degradation: Mitophagy and beyond.

Louise Uoselis, Thanh Ngoc Nguyen, Michael Lazarou.

  Mitochondria are central hubs of cellular metabolism that also play key roles in signaling and disease. It is therefore fundamentally important that mitochondrial quality and activity are tightly regulated. Mitochondrial degradation pathways contribute to quality control of mitochondrial networks and can also regulate the metabolic profile of mitochondria to ensure cellular homeostasis. Here, we cover the many and varied ways in which cells degrade or remove their unwanted mitochondria, ranging from mitophagy to mitochondrial extrusion. The molecular signals driving these varied pathways are discussed, including the cellular and physiological contexts under which the different degradation pathways are engaged.

Keywords:  MDV; PINK1; Parkin; degradation; mitochondria; mitochondrial quality control; mitophagy; proteasome; selective autophagy; ubiquitin

DOI:  https://doi.org/10.1016/j.molcel.2023.08.021
IUBMB Life. 2023 Sep 15.

Early steps in the biogenesis of mitochondrially encoded oxidative phosphorylation subunits.

Sung-Jun Jung, Sagar Sridhara, Martin Ott.

  The complexes mediating oxidative phosphorylation (OXPHOS) in the inner mitochondrial membrane consist of proteins encoded in the nuclear or the mitochondrial DNA. The mitochondrially encoded membrane proteins (mito-MPs) represent the catalytic core of these complexes and follow complicated pathways for biogenesis. Owing to their overall hydrophobicity, mito-MPs are co-translationally inserted into the inner membrane by the Oxa1 insertase. After insertion, OXPHOS biogenesis factors mediate the assembly of mito-MPs into complexes and participate in the regulation of mitochondrial translation, while protein quality control factors recognize and degrade faulty or excess proteins. This review summarizes the current understanding of these early steps occurring during the assembly of mito-MPs by concentrating on results obtained in the model organism baker's yeast.

Keywords:  eukaryotic gene expression; mitochondria; protein folding; protein synthesis

DOI:  https://doi.org/10.1002/iub.2784
Front Cell Dev Biol. 2023 ;11 1270341

PKR activation in mitochondrial unfolded protein response-mitochondrial dsRNA might do the trick.

Eva Rath.



Keywords:  double-stranded RNA-activated protein kinase; doublestranded RNA; inflammatory bowel diseases; integrated stress response; mitochondria; mitochondrial unfolded protein response; proteostasis; stress signaling

DOI:  https://doi.org/10.3389/fcell.2023.1270341
Endocr Metab Immune Disord Drug Targets. 2023 Sep 14.

Mit.OnOff: A Science Communication Project for Public Awareness about Mitochondrial Cytopathies.

Manuela Grazina, Sara Martins, Maria João Santos, Marta Simões, Carolina Caetano, Beatriz Neves, Sara Varela Amaral, Laurence A Bindoff.

  INTRODUCTION: Mitochondrial diseases are rare, heterogeneous, incurable and complex to diagnose. Probably due to their rareness, there is still a lack of literacy in this area, especially in society, but also in schools and in general, health care services. Accordingly, tools that may bring advancement in science and health literacy are needed. Mit.OnOff is a science communication project based on a bilateral partnership between the University of Coimbra (Portugal) and the University of Bergen (Norway). It aims to inform society about rare diseases related to mitochondrial cytopathies with an emphasis on LHON.METHODS: The initiative focuses on the creation of an illustrated book explaining the diseases caused by the failure of energy production in simple and accessible language. The aim is to raise awareness (particularly in Portugal and Norway) and provide in-depth knowledge to people suffering from these diseases.
RESULTS/CASE REPORT: This project involves expert scientists in the field of mitochondrial disease, science communicators and artists in alignment with the United Nations SDGs, Agenda 2030. Mit.OnOff is a bilateral partnership (Portugal and Norway) established to address the lack of knowledge and health literacy on the subject of mitochondrial disease. The book will be distributed in both countries, creating a sense of inclusion and visibility and influencing decisions regarding these diseases. It is a relevant educational medium (e.g., schools, health care provision). The distribution of the book is complemented with other communication materials. Oral communications are made, together with public involvement, in which special glasses will be distributed to simulate a mitochondrial disease that leads to blindness (LHON) for the public to experience what it is like living with a rare disease.
CONCLUSION: It is hoped that the production of this book will give patients a sense of inclusion and representation in the media. This, in turn, will contribute to achieving the SDG targets (3,4,5,8,10,12), i.e., ensuring people live healthy lives, reducing child mortality, and increasing life expectancy, ensuring access to inclusive, equitable and quality education for all, ensuring gender equality, and contributing to a peaceful and prosperous world.

Keywords:  LHON; health literacy; mitochondria; mitochondrial cytopathies; mitochondrial diseases; rare diseases; science communication

DOI:  https://doi.org/10.2174/1871530323666230914114434
Cold Spring Harb Mol Case Stud. 2023 Sep 14. pii: mcs.a006295. [Epub ahead of print]

Novel pathogenic UQCRC2 variants in a female with normal neurodevelopment.

Lea Abou Haidar, Robert Charles Harris, Panayotis Pachnis, Hongli Chen, Garrett K Gotway, Min Ni, Ralph J DeBerardinis.

  Electron transport chain (ETC) disorders are a group of rare, multisystem diseases caused by impaired oxidative phosphorylation and energy production. Deficiencies in complex III (CIII), also known as ubiquinol-cytochrome c reductase, are particularly rare in humans. Ubiquinol-cytochrome c reductase core protein 2 (UQCRC2) encodes a subunit of CIII that plays a crucial role in dimerization. Several pathogenic UQCRC2 variants have been identified in patients presenting with metabolic abnormalities that include lactic acidosis, hyperammonemia, hypoglycemia, and organic aciduria. Almost all previously-reported UQCRC2-deficient patients exhibited neurodevelopmental involvement, including developmental delays and structural brain anomalies. Here we describe a girl who presented at 3 years of age with lactic acidosis, hyperammonemia, and hypoglycemia, but has not shown any evidence of neurodevelopmental dysfunction by age 15. Whole exome sequencing revealed compound heterozygosity for two novel variants in UQCRC2: c.1189G>A; p.Gly397Arg and c.437T>C; p.Phe146Ser. Here, we discuss the patient's clinical presentation and the likely pathogenicity of these two missense variants.

Keywords:  Acute hyperammonemia; Decreased activity of mitochondrial complex III; Fasting hypoglycemia; Stress/infection-induced lactic acidosis

DOI:  https://doi.org/10.1101/mcs.a006295
Neurobiol Dis. 2023 Sep 11. pii: S0969-9961(23)00303-0. [Epub ahead of print] 106288

Elevated susceptibility to exogenous seizure triggers and impaired interneuron excitability in a mouse model of Leigh syndrome epilepsy.

Arena Manning, Victor Han, Alexa Stephens, Rose Wang, Nicholas Bush, Michelle Bard, Jan M Ramirez, Franck Kalume.

  Mutations in the NADH dehydrogenase (ubiquinone reductase) iron‑sulfur protein 4 (NDUFS4) gene, which encodes for a key structural subunit of the OXFOS complex I (CI), lead to the most common form of mitochondrial disease in children known as Leigh syndrome (LS). As in other mitochondrial diseases, epileptic seizures constitute one of the most significant clinical features of LS. These seizures are often very difficult to treat and are a sign of poor disease prognosis. Mice with whole-body Ndufs4 KO are a well-validated model of LS; they exhibit epilepsy and several other clinical features of LS. We have previously shown that mice with Ndufs4 KO in only GABAergic interneurons (Gad2-Ndufs4-KO) reproduce the severe epilepsy phenotype observed in the global KO mice. This observation indicated that these mice represent an excellent model of LS epilepsy isolated from other clinical manifestations of the disease. To further characterize this epilepsy phenotype, we investigated seizure susceptibility to selected exogenous seizure triggers in Gad2-Ndufs4-KO mice. Then, using electrophysiology, imaging, and immunohistochemistry, we studied the cellular, physiological, and neuroanatomical consequences of Ndufs4 KO in GABAergic interneurons. Homozygous KO of Ndufs4 in GABAergic interneurons leads to a prominent susceptibility to exogenous seizure triggers, impaired interneuron excitability and interneuron loss. Finally, we found that the hippocampus and cortex participate in the generation of seizure activity in Gad2-Ndufs4-KO mice. These findings further define the LS epilepsy phenotype and provide important insights into the cellular mechanisms underlying epilepsy in LS and other mitochondrial diseases.

Keywords:  Epilepsy; Excitability; GABAergic interneuron; Ndufs4; Seizures; hippocampus

DOI:  https://doi.org/10.1016/j.nbd.2023.106288
Biosens Bioelectron. 2023 Sep 09. pii: S0956-5663(23)00618-8. [Epub ahead of print]241 115676

RatioCRISPR: A ratiometric biochip based on CRISPR/Cas12a for automated and multiplexed detection of heteroplasmic SNPs in mitochondrial DNA.

Xiaolong Wu, Yi Zhao, Chuanghao Guo, Conghui Liu, Qianling Zhang, Yong Chen, Yizhen Liu, Xueji Zhang.

Mitochondrial genetic diseases are often characterized by heteroplasmic single nucleotide polymorphisms (SNPs) where both wild-type (WT) and mutant-type (MT) coexist, making detection of accurate SNP abundance critical for diagnosis. Here, we present RatioCRISPR, an automated ratiometric biochip sensor based on the CRISPR/Cas12a system for detecting multiple heteroplasmic SNPs in mitochondrial DNA (mtDNA). The ratiometric sensor output is only influenced by the relative abundance of WT and MT, with minimal impact from sample concentration. Biochips allow the simultaneous detection of multiple SNP sites for more accurate disease diagnosis. RatioCRISPR can accurately detect 8 samples simultaneously within 25 min with a limit of detection (LOD) of 15.7 aM. We successfully detected 13 simulated samples of three mtDNA point mutations (m.3460G>A, m.11778G>A, and m.14484T>C), which lead to Leber's hereditary optic neuropathy (LHON) and set a threshold (60%) of heteroplasmy to evaluate disease risk. This automated and accurate biosensor has broad applications in diagnosing multiple SNPs, especially those with heteroplasmic variations, making it an advanced and convenient tool for mtDNA disease diagnosis.

DOI: https://doi.org/10.1016/j.bios.2023.115676
Neurohospitalist. 2023 Oct;13(4): 448-449

Bilateral and Symmetrical Basal Ganglia Calcifications May Aid in Mitochondrial Disease Diagnosis in Resource-Limited Settings.

Amado Jiménez-Ruiz, Victor Aguilar-Fuentes, Fátima Gabriela Macías-Ortíz, José Luis Ruiz-Sandoval.



Keywords:  Cognitive impairment ; Epilepsy; MELAS; Mitochondrial disease; Seizures; Stroke and Cerebrovascular Disease

DOI:  https://doi.org/10.1177/19418744231173831
Cell Rep. 2023 Sep 13. pii: S2211-1247(23)01143-9. [Epub ahead of print]42(9): 113131

Cold-stimulated brown adipose tissue activation is related to changes in serum metabolites relevant to NAD+ metabolism in humans.

Mueez U-Din, Vanessa D de Mello, Marjo Tuomainen, Juho Raiko, Tarja Niemi, Tobias Fromme, Anton Klåvus, Nadine Gautier, Kimmo Haimilahti, Marko Lehtonen, Karsten Kristiansen, John W Newman, Kirsi H Pietiläinen, Jussi Pihlajamäki, Ez-Zoubir Amri, Martin Klingenspor, Pirjo Nuutila, Eija Pirinen, Kati Hanhineva, Kirsi A Virtanen.

  Cold-induced brown adipose tissue (BAT) activation is considered to improve metabolic health. In murine BAT, cold increases the fundamental molecule for mitochondrial function, nicotinamide adenine dinucleotide (NAD+), but limited knowledge of NAD+ metabolism during cold in human BAT metabolism exists. We show that cold increases the serum metabolites of the NAD+ salvage pathway (nicotinamide and 1-methylnicotinamide) in humans. Additionally, individuals with cold-stimulated BAT activation have decreased levels of metabolites from the de novo NAD+ biosynthesis pathway (tryptophan, kynurenine). Serum nicotinamide correlates positively with cold-stimulated BAT activation, whereas tryptophan and kynurenine correlate negatively. Furthermore, the expression of genes involved in NAD+ biosynthesis in BAT is related to markers of metabolic health. Our data indicate that cold increases serum tryptophan conversion to nicotinamide to be further utilized by BAT. We conclude that NAD+ metabolism is activated upon cold in humans and is probably regulated in a coordinated fashion by several tissues.

Keywords:  BAT; CP: Metabolism; NAD(+); cold exposure; human brown adipose tissue; nicotinamide; tryptophan

DOI:  https://doi.org/10.1016/j.celrep.2023.113131
J Cell Biol. 2023 Oct 02. pii: e202309037. [Epub ahead of print]222(10):

A nucleotide diphosphate kinase mediates tethering between mitochondria prior to fusion.

Arisa Ikeda, Miho Iijima, Hiromi Sesaki.

Mitochondrial fusion plays an important role in both their structure and function. In this issue, Su et al. (2023. J. Cell Biol.https://doi.org/10.1083/jcb.202301091) report that a nucleoside diphosphate kinase, NME3, facilitates mitochondrial tethering prior to fusion through its direct membrane-binding and hexamerization but not its kinase activity.

DOI: https://doi.org/10.1083/jcb.202309037
Dev Cell. 2023 Sep 07. pii: S1534-5807(23)00435-5. [Epub ahead of print]

Mitochondrial GTP metabolism controls reproductive aging in C. elegans.

Yi-Tang Lee, Marzia Savini, Tao Chen, Jin Yang, Qian Zhao, Lang Ding, Shihong Max Gao, Mumine Senturk, Jessica N Sowa, Jue D Wang, Meng C Wang.

  Healthy mitochondria are critical for reproduction. During aging, both reproductive fitness and mitochondrial homeostasis decline. Mitochondrial metabolism and dynamics are key factors in supporting mitochondrial homeostasis. However, how they are coupled to control reproductive health remains unclear. We report that mitochondrial GTP (mtGTP) metabolism acts through mitochondrial dynamics factors to regulate reproductive aging. We discovered that germline-only inactivation of GTP- but not ATP-specific succinyl-CoA synthetase (SCS) promotes reproductive longevity in Caenorhabditis elegans. We further identified an age-associated increase in mitochondrial clustering surrounding oocyte nuclei, which is attenuated by GTP-specific SCS inactivation. Germline-only induction of mitochondrial fission factors sufficiently promotes mitochondrial dispersion and reproductive longevity. Moreover, we discovered that bacterial inputs affect mtGTP levels and dynamics factors to modulate reproductive aging. These results demonstrate the significance of mtGTP metabolism in regulating oocyte mitochondrial homeostasis and reproductive longevity and identify mitochondrial fission induction as an effective strategy to improve reproductive health.

Keywords:  GTP metabolism; bacteria-host interaction; gene-environment interaction; mitochondrial distribution; mitochondrial dynamics; oocyte quality control; reproductive aging; succinyl-CoA synthetase; vitamin B12

DOI:  https://doi.org/10.1016/j.devcel.2023.08.019
Life Sci Alliance. 2023 Dec;pii: e202302091. [Epub ahead of print]6(12):

Mitochondrial membrane potential acts as a retrograde signal to regulate cell cycle progression.

Choco Michael Gorospe, Gustavo Carvalho, Alicia Herrera Curbelo, Lisa Marchhart, Isabela C Mendes, Katarzyna Niedźwiecka, Paulina H Wanrooij.

Mitochondria are central to numerous metabolic pathways whereby mitochondrial dysfunction has a profound impact and can manifest in disease. The consequences of mitochondrial dysfunction can be ameliorated by adaptive responses that rely on crosstalk from the mitochondria to the rest of the cell. Such mito-cellular signalling slows cell cycle progression in mitochondrial DNA-deficient (ρ0) Saccharomyces cerevisiae cells, but the initial trigger of the response has not been thoroughly studied. Here, we show that decreased mitochondrial membrane potential (ΔΨm) acts as the initial signal of mitochondrial stress that delays G1-to-S phase transition in both ρ0 and control cells containing mtDNA. Accordingly, experimentally increasing ΔΨm was sufficient to restore timely cell cycle progression in ρ0 cells. In contrast, cellular levels of oxidative stress did not correlate with the G1-to-S delay. Restored G1-to-S transition in ρ0 cells with a recovered ΔΨm is likely attributable to larger cell size, whereas the timing of G1/S transcription remained delayed. The identification of ΔΨm as a regulator of cell cycle progression may have implications for disease states involving mitochondrial dysfunction.

DOI: https://doi.org/10.26508/lsa.202302091
Trends Biochem Sci. 2023 Sep 11. pii: S0968-0004(23)00213-X. [Epub ahead of print]

Using light to drive energy transduction in metazoan aging.

Vaibhav Tiwary, Anne-Marie Galow, Andrew P Wojtovich, Shahaf Peleg.

  Mitochondrial dysfunction is a central hallmark of aging and energy transduction is a promising target for longevity interventions. New research suggests that interventions in how energy is transduced could benefit healthy longevity. Here, we propose using light as an alternative energy source to fuel mitochondria and increase metazoan lifespan.

Keywords:  bioenergetics; lifespan; metabolism; mitochondria; optogenetics; proton pump

DOI:  https://doi.org/10.1016/j.tibs.2023.08.010
Radiol Cardiothorac Imaging. 2023 Aug;5(4): e230144

Mitochondrial Cardiomyopathy Due to the MT-TI Variant m.4300A>G Requires Comprehensive Clinical and Genetic Workup.

Josef Finsterer.

DOI: https://doi.org/10.1148/ryct.230144
Eur Heart J Case Rep. 2023 Sep;7(9): ytad440

Successful transcatheter mitral valve repair for functional mitral regurgitation in a patient with mitochondrial cardiomyopathy: a case report.

Takashi Hiruma, Mike Saji, Mamoru Nanasato, Mitsuaki Isobe.

  Background: Mitochondrial diseases are a group of genetic disorders caused by nuclear or mitochondrial DNA gene mutations and characterized by multiorgan disorders, including cardiomyopathy. Mitochondrial cardiomyopathy is occasionally complicated by hypertrophic cardiomyopathy with/without left ventricular systolic dysfunction, dilated cardiomyopathy, and left ventricular non-compaction. In such cases, the dilated left ventricle impairs coaptation of the mitral leaflets and leads to functional mitral regurgitation. To date, valvular interventions in patients with mitochondrial cardiopathy have not been investigated.Case summary: A 64-year-old woman with mitochondrial cardiopathy was referred to our hospital owing to dyspnoea. She experienced her first admission with heart failure at age 60 years. At 62 years old, she was diagnosed with maternally inherited diabetes and deafness with mitochondrial cardiomyopathy based on mitochondrial DNA sequencing. Despite administration of guideline-directed medical therapy and high-dose taurine supplementation, she was repeatedly hospitalized for heart failure. At admission, transthoracic echocardiography revealed severe functional mitral regurgitation due to left ventricular dilatation. Surgical risk was considered high (Society of Thoracic Surgeons score of 12.6%); therefore, transcatheter edge-to-edge repair with the MitraClip system was performed. Two devices deployed at the middle segment of the anterior and posterior leaflet successfully reduced mitral regurgitation. The patient was free from cardiovascular events during the 2-year follow-up period.
Discussion: Transcatheter edge-to-edge repair is a less invasive and effective treatment for severe drug-refractory mitral regurgitation in patients with mitochondrial disease. Given the limited therapeutic options for mitochondrial cardiopathy, further studies are required to uncover the mechanism underlying mitochondrial diseases and establish disease-specific treatments.

Keywords:  Case report; Heart failure; Maternally inherited diabetes and deafness; Mitochondrial cardiomyopathy; Mitral regurgitation; Transcatheter edge-to-edge repair

DOI:  https://doi.org/10.1093/ehjcr/ytad440
Dis Model Mech. 2023 Sep 11. pii: dmm.050114. [Epub ahead of print]

Comparative multi-omics analyses of cardiac mitochondrial stress in three mouse models of frataxin deficiency.

Nicole M Sayles, Jill S Napierala, Josef Anrather, Nadège Diedhiou, Jixue Li, Marek Napierala, Hélène Puccio, Giovanni Manfredi.

  Cardiomyopathy is often fatal in Friedreich Ataxia (FA). However, FA hearts maintain adequate function until advanced disease stages, suggesting initial adaptation to the loss of frataxin (FXN). Conditional cardiac knockout mouse models of FXN show transcriptional and metabolic profiles of the mitochondrial integrated stress response (ISRmt), which could play an adaptive role. However, ISRmt has not been investigated in models with disease-relevant, partial decrease of FXN. We characterized the heart transcriptomes and metabolomes of three mouse models with varying degrees of FXN depletion, YG8-800, KIKO-700, and FxnG127V. Few metabolites were changed in YG8-800 mice and did not provide a signature of cardiomyopathy or ISRmt. Instead, several metabolites were altered in FxnG127V and KIKO-700 hearts. Transcriptional changes were found in all models, but differentially expressed genes consistent with cardiomyopathy and ISRmt were only identified in FxnG127V hearts. However, these changes were surprisingly mild even at an advanced age (18-months), despite a severe decrease in FXN levels to 1% of WT. These findings indicate that the mouse heart has low reliance on FXN, highlighting the difficulty in modeling genetically relevant FA cardiomyopathy.

Keywords:  Cardiomyopathy; Frataxin; Friedreich Ataxia; Integrated stress response; Mitochondria; Mouse model

DOI:  https://doi.org/10.1242/dmm.050114
Mol Cell. 2023 Sep 06. pii: S1097-2765(23)00651-2. [Epub ahead of print]

Global analysis of aging-related protein structural changes uncovers enzyme-polymerization-based control of longevity.

Jurgita Paukštytė, Rosa María López Cabezas, Yuehan Feng, Kai Tong, Daniela Schnyder, Ellinoora Elomaa, Pavlina Gregorova, Matteo Doudin, Meeri Särkkä, Jesse Sarameri, Alice Lippi, Helena Vihinen, Juhana Juutila, Anni Nieminen, Petri Törönen, Liisa Holm, Eija Jokitalo, Anita Krisko, Juha Huiskonen, L Peter Sarin, Ville Hietakangas, Paola Picotti, Yves Barral, Juha Saarikangas.

  Aging is associated with progressive phenotypic changes. Virtually all cellular phenotypes are produced by proteins, and their structural alterations can lead to age-related diseases. However, we still lack comprehensive knowledge of proteins undergoing structural-functional changes during cellular aging and their contributions to age-related phenotypes. Here, we conducted proteome-wide analysis of early age-related protein structural changes in budding yeast using limited proteolysis-mass spectrometry (LiP-MS). The results, compiled in online ProtAge catalog, unraveled age-related functional changes in regulators of translation, protein folding, and amino acid metabolism. Mechanistically, we found that folded glutamate synthase Glt1 polymerizes into supramolecular self-assemblies during aging, causing breakdown of cellular amino acid homeostasis. Inhibiting Glt1 polymerization by mutating the polymerization interface restored amino acid levels in aged cells, attenuated mitochondrial dysfunction, and led to lifespan extension. Altogether, this comprehensive map of protein structural changes enables identifying mechanisms of age-related phenotypes and offers opportunities for their reversal.

Keywords:  aging; amino acid; functional proteomics; limited proteolysis; mass spectrometry; polymerization; self-assembly; structural change; structural proteomics; yeast

DOI:  https://doi.org/10.1016/j.molcel.2023.08.015
Brain. 2023 Sep 13. pii: awad313. [Epub ahead of print]

Trazodone rescues dysregulated synaptic and mitochondrial nascent proteomes in prion neurodegeneration.

Hector Albert-Gasco, Heather L Smith, Beatriz Alvarez-Castelao, Dean Swinden, Mark Halliday, Sudha Janaki-Raman, Adrian Butcher, Giovanna R Mallucci.

  The unfolded protein response (UPR) is rapidly gaining momentum as a therapeutic target for protein misfolding neurodegenerative diseases, in which its overactivation results in sustained translational repression leading to synapse loss and neurodegeneration. In mouse models of these disorders, from Alzheimer's to prion disease, modulation of the pathway - including by the licensed drug, trazodone - restores global protein synthesis rates with profound neuroprotective effects. However, the precise nature of the translational impairment, in particular the specific proteins affected in disease, and their response to therapeutic UPR modulation are poorly understood. We used non-canonical amino acid tagging (NCAT) to measure de novo protein synthesis in the brains of prion-diseased mice with and without trazodone treatment, in both whole hippocampus and cell-specifically. During disease the predominant nascent proteome changes occur in synaptic, cytoskeletal and mitochondrial proteins in both hippocampal neurons and astrocytes. Remarkably, trazodone treatment for just two weeks largely restored the whole disease nascent proteome in the hippocampus to that of healthy, uninfected mice, predominantly with recovery of proteins involved in synaptic and mitochondrial function. In parallel, trazodone treatment restored the disease-associated decline in synapses and mitochondria and their function to wildtype levels. In conclusion, this study increases our understanding of how translational repression contributes to neurodegeneration through synaptic and mitochondrial toxicity via depletion of key proteins essential for their function. Further, it provides new insights into the neuroprotective mechanisms of trazodone through reversal of this toxicity, relevant for the treatment of neurodegenerative diseases via translational modulation.

Keywords:  UPR/ISR; mitochondria; nascent proteome; neurodegeneration; synapses; translational repression; trazodone

DOI:  https://doi.org/10.1093/brain/awad313
Free Radic Biol Med. 2023 Sep 13. pii: S0891-5849(23)00627-5. [Epub ahead of print]

Nrf2 depletion in the context of loss-of-function Keap1 leads to mitolysosome accumulation.

Sharadha Dayalan Naidu, Plamena R Angelova, Elena V Knatko, Chiara Leonardi, Miroslav Novak, Laureano de la Vega, Ian G Ganley, Andrey Y Abramov, Albena T Dinkova-Kostova.

Transcription factor nuclear factor erythroid 2 p45-related factor 2 (Nrf2) is the principal determinant of the cellular redox homeostasis, contributing to mitochondrial function, integrity and bioenergetics. The main negative regulator of Nrf2 is Kelch-like ECH associated protein 1 (Keap1), a substrate adaptor for Cul3/Rbx1 ubiquitin ligase, which continuously targets Nrf2 for ubiquitination and proteasomal degradation. Loss-of-function mutations in Keap1 occur frequently in lung cancer, leading to constitutive Nrf2 activation. We used the human lung cancer cell line A549 and its CRISPR/Cas9-generated homozygous Nrf2-knockout (Nrf2-KO) counterpart to assess the role of Nrf2 on mitochondrial health. To confirm that the observed effects of Nrf2 deficiency are not due to clonal selection or long-term adaptation to the absence of Nrf2, we also depleted Nrf2 by siRNA (siNFE2L2), thus creating populations of Nrf2-knockdown (Nrf2-KD) A549 cells. Nrf2 deficiency decreased mitochondrial respiration, but increased the mitochondrial membrane potential, mass, DNA content, and the number of mitolysosomes. The proportion of ATG7 and ATG3 within their respective LC3B conjugates was increased in Nrf2-deficient cells with mutant Keap1, whereas the formation of new autophagosomes was not affected. Thus, in lung cancer cells with loss-of-function Keap1, Nrf2 facilitates mitolysosome degradation thereby ensuring timely clearance of damaged mitochondria.

DOI: https://doi.org/10.1016/j.freeradbiomed.2023.09.009
Nat Metab. 2023 Sep 11.

Dynamic lipidome alterations associated with human health, disease and ageing.

Daniel Hornburg, Si Wu, Mahdi Moqri, Xin Zhou, Kevin Contrepois, Nasim Bararpour, Gavin M Traber, Baolong Su, Ahmed A Metwally, Monica Avina, Wenyu Zhou, Jessalyn M Ubellacker, Tejaswini Mishra, Sophia Miryam Schüssler-Fiorenza Rose, Paula B Kavathas, Kevin J Williams, Michael P Snyder.

Lipids can be of endogenous or exogenous origin and affect diverse biological functions, including cell membrane maintenance, energy management and cellular signalling. Here, we report >800 lipid species, many of which are associated with health-to-disease transitions in diabetes, ageing and inflammation, as well as cytokine-lipidome networks. We performed comprehensive longitudinal lipidomic profiling and analysed >1,500 plasma samples from 112 participants followed for up to 9 years (average 3.2 years) to define the distinct physiological roles of complex lipid subclasses, including large and small triacylglycerols, ester- and ether-linked phosphatidylethanolamines, lysophosphatidylcholines, lysophosphatidylethanolamines, cholesterol esters and ceramides. Our findings reveal dynamic changes in the plasma lipidome during respiratory viral infection, insulin resistance and ageing, suggesting that lipids may have roles in immune homoeostasis and inflammation regulation. Individuals with insulin resistance exhibit disturbed immune homoeostasis, altered associations between lipids and clinical markers, and accelerated changes in specific lipid subclasses during ageing. Our dataset based on longitudinal deep lipidome profiling offers insights into personalized ageing, metabolic health and inflammation, potentially guiding future monitoring and intervention strategies.

DOI: https://doi.org/10.1038/s42255-023-00880-1
Sci Rep. 2023 Sep 15. 13(1): 15339

Remdesivir increases mtDNA copy number causing mild alterations to oxidative phosphorylation.

Nicole DeFoor, Swagatika Paul, Shuang Li, Erwin K Gudenschwager Basso, Valentina Stevenson, Jack L Browning, Anna K Prater, Samantha Brindley, Ge Tao, Alicia M Pickrell.

SARS-CoV-2 causes the severe respiratory disease COVID-19. Remdesivir (RDV) was the first fast-tracked FDA approved treatment drug for COVID-19. RDV acts as an antiviral ribonucleoside (adenosine) analogue that becomes active once it accumulates intracellularly. It then diffuses into the host cell and terminates viral RNA transcription. Previous studies have shown that certain nucleoside analogues unintentionally inhibit mitochondrial RNA or DNA polymerases or cause mutational changes to mitochondrial DNA (mtDNA). These past findings on the mitochondrial toxicity of ribonucleoside analogues motivated us to investigate what effects RDV may have on mitochondrial function. Using in vitro and in vivo rodent models treated with RDV, we observed increases in mtDNA copy number in Mv1Lu cells (35.26% increase ± 11.33%) and liver (100.27% increase ± 32.73%) upon treatment. However, these increases only resulted in mild changes to mitochondrial function. Surprisingly, skeletal muscle and heart were extremely resistant to RDV treatment, tissues that have preferentially been affected by other nucleoside analogues. Although our data suggest that RDV does not greatly impact mitochondrial function, these data are insightful for the treatment of RDV for individuals with mitochondrial disease.

DOI: https://doi.org/10.1038/s41598-023-42704-y
Nat Metab. 2023 Sep 14.

Complex regulatory processes control exercise adaptations of skeletal muscle.

DOI: https://doi.org/10.1038/s42255-023-00894-9
BMC Cardiovasc Disord. 2023 Sep 15. 23(1): 464

Reversible cardiac function and left ventricular hypertrophy in a Chinese man with mitochondrial myopathy: a case report.

Guiping Wu, Yijun Han, Lifeng Zhao, Hong Zhang, Xiuzhao Fan, Weiqin Li, Xiaowen Che, Yun Zhou.

  BACKGROUND: Mitochondrial myopathies (MMs) are a group of multi-system diseases caused by abnormalities in mitochondrial DNA (mtDNA) or mutations of nuclear DNA (nDNA). The diagnosis of mitochondrial myopathy (MM) is reliant on the combination of history and physical examination, muscle biopsy, histochemical studies, and next-generation sequencing. Patients with MMs have diverse clinical manifestations. In the contemporary literature, there is a paucity of reports on cardiac structure and function in this rare disease. We report a Chinese man with MM accompanied with both acute right heart failure and left ventricular hypertrophy.CASE PRESENTATION: A 49-year-old man presented with clinical features suggestive of MM, i.e., ophthalmoparesis, weakness of the pharyngeal and extremity muscles, and respiratory muscles which gradually progressed to respiratory insufficiency. He had a family history of mitochondrial myopathy. He had increased levels of serum creatine kinase and lactate. Muscle biopsy of left lateral thigh revealed 8% ragged red fibers (RRF) and 42% COX-negative fibers. Gene sequencing revealed a novel heterozygote TK2 variant (NM_001172644: c.584T>C, p.Leu195Pro) and another heterozygous variant (NM_004614.4:c.156+958G>A; rs1965661603) in the intron of TK2 gene. Based on these findings, we diagnosed the patient as a case of MM. Echocardiography revealed right heart enlargement, pulmonary hypertension, left ventricular hypertrophy, and thickening of the main pulmonary artery and its branches. The patient received non-invasive ventilation and coenzyme Q10 (CoQ10). The cardiac structure and function were restored at 1-month follow-up.
CONCLUSIONS: This is the first report of reversible cardiac function impairment and left ventricular hypertrophy in a case of adult-onset MM, nocturnal hypoxia is a potential mechanism for left ventricular hypertrophy in patients with MM.

Keywords:  Heart failure; Left ventricular hypertrophy; Mitochondrial myopathy; Pulmonary artery hypertension; Respiratory failure

DOI:  https://doi.org/10.1186/s12872-023-03444-z
J Biol Chem. 2023 Sep 08. pii: S0021-9258(23)02269-X. [Epub ahead of print] 105241

Cardiolipin prolongs the lifetimes of respiratory proteins in Drosophila flight muscle.

Mindong Ren, Yang Xu, Colin K L Phoon, Hediye Erdjument-Bromage, Thomas A Neubert, Michael Schlame.

  Respiratory complexes and cardiolipins have exceptionally long lifetimes. The fact that they co-localize in mitochondrial cristae raises the questions of whether their longevities have a common cause and whether the longevity of OXPHOS proteins is dependent on cardiolipin. To address these questions, we developed a method to measure side-by-side the half-lives of proteins and lipids in wildtype Drosophila and cardiolipin deficient mutants. We fed adult flies with stable isotope-labeled precursors (13C615N2-lysine or 13C6-glucose) and determined the relative abundance of heavy isotopomers in protein and lipid species by mass spectrometry. To minimize confounding effects of tissue regeneration, we restricted our analysis to the thorax, the bulk of which consists of post-mitotic flight muscles. Analysis of 680 protein and 45 lipid species showed that the subunits of respiratory complexes I-V and the carriers for phosphate and ADP/ATP were among the longest-lived proteins (average half-life of 48±16 days) while the molecular species of cardiolipin were the longest-lived lipids (average half-life of 27±6 days). The remarkable longevity of these crista residents was not shared by all mitochondrial proteins, especially not by those residing in the matrix and the inner boundary membrane. Ablation of cardiolipin synthase, which causes replacement of cardiolipin by phosphatidylglycerol, and ablation of tafazzin, which causes partial replacement of cardiolipin by monolyso-cardiolipin, decreased the lifetimes of the respiratory complexes. Ablation of tafazzin also decreased the lifetimes of the remaining cardiolipin species. These data suggest that an important function of cardiolipin in mitochondria is to protect respiratory complexes from degradation.

Keywords:  Insect; isotopic tracer; lipid-protein interaction; membrane biogenesis; mitochondrial respiratory chain complex

DOI:  https://doi.org/10.1016/j.jbc.2023.105241
J Transl Med. 2023 09 09. 21(1): 613

Mitochondrial dysfunction in neurodegenerative disorders: Potential therapeutic application of mitochondrial transfer to central nervous system-residing cells.

Felipe A Bustamante-Barrientos, Noymar Luque-Campos, María Jesús Araya, Eliana Lara-Barba, Javiera de Solminihac, Carolina Pradenas, Luis Molina, Yeimi Herrera-Luna, Yildy Utreras-Mendoza, Roberto Elizondo-Vega, Ana María Vega-Letter, Patricia Luz-Crawford.

Mitochondrial dysfunction is reiteratively involved in the pathogenesis of diverse neurodegenerative diseases. Current in vitro and in vivo approaches support that mitochondrial dysfunction is branded by several molecular and cellular defects, whose impact at different levels including the calcium and iron homeostasis, energetic balance and/or oxidative stress, makes it difficult to resolve them collectively given their multifactorial nature. Mitochondrial transfer offers an overall solution since it contains the replacement of damage mitochondria by healthy units. Therefore, this review provides an introducing view on the structure and energy-related functions of mitochondria as well as their dynamics. In turn, we summarize current knowledge on how these features are deregulated in different neurodegenerative diseases, including frontotemporal dementia, multiple sclerosis, amyotrophic lateral sclerosis, Friedreich ataxia, Alzheimer´s disease, Parkinson´s disease, and Huntington's disease. Finally, we analyzed current advances in mitochondrial transfer between diverse cell types that actively participate in neurodegenerative processes, and how they might be projected toward developing novel therapeutic strategies.

DOI: https://doi.org/10.1186/s12967-023-04493-w
BMC Bioinformatics. 2023 Sep 13. 24(1): 341

A systematic comparison of human mitochondrial genome assembly tools.

Nirmal Singh Mahar, Rohit Satyam, Durai Sundar, Ishaan Gupta.

  BACKGROUND: Mitochondria are the cell organelles that produce most of the chemical energy required to power the cell's biochemical reactions. Despite being a part of a eukaryotic host cell, the mitochondria contain a separate genome whose origin is linked with the endosymbiosis of a prokaryotic cell by the host cell and encode independent genomic information throughout their genomes. Mitochondrial genomes accommodate essential genes and are regularly utilized in biotechnology and phylogenetics. Various assemblers capable of generating complete mitochondrial genomes are being continuously developed. These tools often use whole-genome sequencing data as an input containing reads from the mitochondrial genome. Till now, no published work has explored the systematic comparison of all the available tools for assembling human mitochondrial genomes using short-read sequencing data. This evaluation is required to identify the best tool that can be well-optimized for small-scale projects or even national-level research.RESULTS: In this study, we have tested the mitochondrial genome assemblers for both simulated datasets and whole genome sequencing (WGS) datasets of humans. For the highest computational setting of 16 computational threads with the simulated dataset having 1000X read depth, MitoFlex took the least execution time of 69 s, and IOGA took the longest execution time of 1278 s. NOVOPlasty utilized the least computational memory of approximately 0.098 GB for the same setting, whereas IOGA utilized the highest computational memory of 11.858 GB. In the case of WGS datasets for humans, GetOrganelle and MitoFlex performed the best in capturing the SNPs information with a mean F1-score of 0.919 at the sequencing depth of 10X. MToolBox and NOVOPlasty performed consistently across all sequencing depths with a mean F1 score of 0.897 and 0.890, respectively.
CONCLUSIONS: Based on the overall performance metrics and consistency in assembly quality for all sequencing data, MToolBox performed the best. However, NOVOPlasty was the second fastest tool in execution time despite being single-threaded, and it utilized the least computational resources among all the assemblers when tested on simulated datasets. Therefore, NOVOPlasty may be more practical when there is a significant sample size and a lack of computational resources. Besides, as long-read sequencing gains popularity, mitochondrial genome assemblers must be developed to use long-read sequencing data.

Keywords:  Assembly; Benchmark; Genome; Mitochondria

DOI:  https://doi.org/10.1186/s12859-023-05445-3
Cell Rep Methods. 2023 Sep 05. pii: S2667-2375(23)00224-2. [Epub ahead of print] 100580

Atlas of primary cell-type-specific sequence models of gene expression and variant effects.

Ksenia Sokolova, Chandra L Theesfeld, Aaron K Wong, Zijun Zhang, Kara Dolinski, Olga G Troyanskaya.

  Human biology is rooted in highly specialized cell types programmed by a common genome, 98% of which is outside of genes. Genetic variation in the enormous noncoding space is linked to the majority of disease risk. To address the problem of linking these variants to expression changes in primary human cells, we introduce ExPectoSC, an atlas of modular deep-learning-based models for predicting cell-type-specific gene expression directly from sequence. We provide models for 105 primary human cell types covering 7 organ systems, demonstrate their accuracy, and then apply them to prioritize relevant cell types for complex human diseases. The resulting atlas of sequence-based gene expression and variant effects is publicly available in a user-friendly interface and readily extensible to any primary cell types. We demonstrate the accuracy of our approach through systematic evaluations and apply the models to prioritize ClinVar clinical variants of uncertain significance, verifying our top predictions experimentally.

Keywords:  CP: Systems biology; deep learning; functional genomics; gene expression prediction; human disease; variant effects

DOI:  https://doi.org/10.1016/j.crmeth.2023.100580
JIMD Rep. 2023 Sep;64(5): 360-366

Fasting and non-fasting plasma levels of monomethyl branched chain fatty acids: Implications for maple syrup urine disease.

Trine Tangeraas, Erle Kristensen, Lars Mørkrid, Elisabeth Elind, Yngve Thomas Bliksrud, Lars Eide.

  The branched-chain amino acids (BCAA) leucine, valine, and isoleucine provide precursors for monomethyl branched-chain fatty acids (BCFA). Established reference ranges for BCFAs are lacking. In maple syrup urine disease (MSUD), a rare inborn error of BCAA metabolism, the endogen production is impaired and MSUD patients are treated with a low protein (low BCAA) diet. The protein restriction may affect the dietary intake of BCFA, depending on the dietary choices made. Patients with MSUD are prescribed a more or less protein-restricted diet depending on the severity of the disease. The combination of a protein-restricted diet and subsequent impaired endogenous synthesis may render MSUD patients sensitive to BCFA deficiency, with yet unknown implications. To investigate the possibility of lower circulatory BCFA levels in MSUD that favors dietary BCFA supplementation, we first established fasting-state reference ranges for selected BCFAs and saturated/unsaturated fatty acids in plasma. Then, the effect of fasting on BCFA levels was evaluated by comparing the distribution in a fasting versus a non-fasting cohort. To test the hypothesis that BCFA deficiency could contribute to MSUD pathophysiology, we recruited patients with intermittent, intermediate, and classical form of MSUD and analyzed the corresponding BCFA z-scores. None of the BCFA species had |z-scores| > 2 relative to the reference range. Our findings do not support the requirement of BCFA supplementation in MSUD patients. The origin of BCFAs is discussed. Impaired capacity to synthesize BCFA do not manifest as reduced plasma levels in MSUD, suggesting that endogenous synthesis is dispensable for plasma levels.

Keywords:  MSUD; fasting; isoleucine; leucine; monomethyl branched‐chain fatty acids; valine

DOI:  https://doi.org/10.1002/jmd2.12380
Mol Metab. 2023 Sep 08. pii: S2212-8778(23)00136-9. [Epub ahead of print] 101802

Partial Skeletal Muscle-Specific Drp1 Knockout Enhances Insulin Sensitivity in Diet-Induced Obese Mice, But Not in Lean Mice.

Benjamin A Kugler, Jared Lourie, Nicolas Berger, Nana Lin, Paul Nguyen, Edzana DosSantos, Abir Ali, Amira Sesay, H Grace Rosen, Baby Kalemba, Gregory M Hendricks, Joseph A Houmard, Hiromi Sesaki, Philimon Gona, Tongjian You, Zhen Yan, Kai Zou.

  OBJECTIVE: Dynamin-related protein 1 (Drp1) is the key regulator of mitochondrial fission. We and others have reported a strong correlation between enhanced Drp1 activity and impaired skeletal muscle insulin sensitivity. This study aimed to determine whether Drp1 directly regulates skeletal muscle insulin sensitivity and whole-body glucose homeostasis.METHODS: We employed tamoxifen-inducible skeletal muscle-specific heterozygous Drp1 knockout mice (mDrp1+/-). Male mDrp1+/- and wildtype (WT) mice were fed with either a high-fat diet (HFD) or low-fat diet (LFD) for four weeks, followed by tamoxifen injections for five consecutive days, and remained on their respective diet for another four weeks. In addition, we used primary human skeletal muscle cells (HSkMC) from lean, insulin-sensitive, and severely obese, insulin-resistant humans and transfected the cells with either a Drp1 shRNA (shDrp1) or scramble shRNA construct. Skeletal muscle and whole-body insulin sensitivity, skeletal muscle insulin signaling, mitochondrial network morphology, respiration, and H2O2 production were measured.
RESULTS: Partial deletion of the Drp1 gene in skeletal muscle led to improved whole-body glucose tolerance and insulin sensitivity (P<0.05) in diet-induced obese, insulin-resistant mice but not in lean mice. Analyses of mitochondrial structure and function revealed that the partial deletion of the Drp1 gene restored mitochondrial dynamics, improved mitochondrial morphology, and reduced mitochondrial Complex I- and II-derived H2O2 (P<0.05) under the condition of diet-induced obesity. In addition, partial deletion of Drp1 in skeletal muscle resulted in elevated circulating FGF21 (P<0.05) and in a trend towards increase of FGF21 expression in skeletal muscle tissue (P=0.095). In primary myotubes derived from severely obese, insulin-resistant humans, ShRNA-induced-knockdown of Drp1 resulted in enhanced insulin signaling, insulin-stimulated glucose uptake and reduced cellular reactive oxygen species (ROS) content compared to the shScramble-treated myotubes from the same donors (P<0.05).
CONCLUSION: These data demonstrate that partial loss of skeletal muscle-specific Drp1 expression is sufficient to improve whole-body glucose homeostasis and insulin sensitivity under obese, insulin-resistant conditions, which may be, at least in part, due to reduced mitochondrial H2O2 production. In addition, our findings revealed divergent effects of Drp1 on whole-body metabolism under lean healthy or obese insulin-resistant conditions in mice.

Keywords:  Insulin sensitivity; Mitochondrial H (2)O(2); Mitochondrial dynamics; Mitochondrial fission

DOI:  https://doi.org/10.1016/j.molmet.2023.101802
Nat Biotechnol. 2023 Sep;41(9): 1183

Parkinson's iPSC trial.

DOI: https://doi.org/10.1038/s41587-023-01965-8
Mitochondrion. 2023 Sep 12. pii: S1567-7249(23)00082-X. [Epub ahead of print]

The Parkinson's disease-associated mutation LRRK2 G2385R alters mitochondrial biogenesis via the PGC-1α-TFAM pathway.

Jian Xue, Jinbao Zhang, Jinru Zhang, Junyi Liu, Fen Wang, Kai Li, Chunfeng Liu.

  Mutations in the Leucine-rich repeat protein kinase 2 (LRRK2) gene are the most frequent cause of familial Parkinson's disease (PD). Although LRRK2 has been extensively studied, the pathogenic mechanism of the LRRK2 G2385R mutation, which is most common in Asian populations, especially in the Chinese Han population, remains unclear. In this study, we demonstrated that the LRRK2 G2385R mutation in HEK293T cells led to a reduction in cellular PGC-1α protein expression and inhibition of mitochondrial biogenesis through the PGC-1α-TFAM pathway. This resulted in a decrease in mitochondrial genome expression, which in turn impaired the normal electron transfer process of the oxidative phosphorylation respiratory chain, leading to mitochondrial dysfunction and onset of apoptosis. The mitochondrial dysfunction and apoptosis caused by the LRRK2 G2385R mutation were significantly alleviated by antioxidant Idebenone, which provides a theoretical basis for the subsequent development of precise treatment specifically for PD patients with LRRK2 G2385R mutation. Further validation of our findings in neurons and animal models are necessary.

Keywords:  Idebenone; LRRK2 G2385R; Mitochondrial biogenesis; Mitochondrial dysfunction; Parkinson’s disease

DOI:  https://doi.org/10.1016/j.mito.2023.09.002
J Med Chem. 2023 Sep 11.

Discovery of a First-in-Class CD38 Inhibitor for the Treatment of Mitochondrial Myopathy.

Yue Li, Yuanyuan Liu, Yong Zhang, Yong Wu, Zili Xing, JianFei Wang, Guo-Huang Fan.

CD38 is a crucial NADase in mammalian tissues that degrades NAD+ and thus regulates cellular NAD+ levels. Abnormal CD38 expression is linked to mitochondrial dysfunction under several pathological conditions. We present a novel CD38 inhibitor, compound 1, with high potency for CD38 (IC50 of 11 nM) and minimal activity against other targets. In a Pus1 knockout (Pus1-/-) mouse model of mitochondrial myopathy, compound 1 treatment rescued the decline in running endurance in a dose-dependent manner, associated with an elevated NAD+ level in muscle tissue, increased expression of Nrf2, which is known to promote mitochondrial biogenesis, and reduced lactate production. RNA sequencing data indicated that compound 1 has a great effect on mitochondrial function, metabolic processes, muscle contraction/development, and actin filament organization via regulating the expression of relevant genes. Compound 1 is a promising candidate for its excellent in vivo efficacy, favorable pharmacokinetics, and attractive safety profile.

DOI: https://doi.org/10.1021/acs.jmedchem.3c00391
J Parkinsons Dis. 2023 ;13(6): 853-866

Clinical Trial Highlights: Modulators of Mitochondrial Function.

Francesco Capriglia, Toby Burgess, Oliver Bandmann, Heather Mortiboys.

DOI: https://doi.org/10.3233/JPD-239003
Br J Pharmacol. 2023 Sep 15.

NRF2 signaling in cytoprotection and metabolism.

Shohei Murakami, Yusuke Kusano, Keito Okazaki, Takaaki Akaike, Hozumi Motohashi.

The KEAP1-NRF2 system plays a central role in cytoprotection and defense mechanisms against oxidative stress. Because KEAP1 serves as a biosensor for electrophiles by using its reactive thiols and because NRF2 is a transcriptional factor regulating genes involved in the sulfur-mediated redox reactions, the KEAP1-NRF2 system has been regarded as a sulfur-utilizing cytoprotective mechanism. NRF2 is a key regulator of cytoprotective genes, such as antioxidant and detoxification genes, and also to possess potent anti-inflammatory activity. NRF2 has been recently focused as a regulator for the cellular metabolism and mitochondrial function. Particularly, the NRF2-mediated regulatory mechanisms of metabolites and mitochondria has been considered diverse but has not been fully clarified yet. This review article provides an overview of the molecular mechanisms that regulate NRF2 signaling and its cytoprotective roles, and also highlights NRF2 contribution to the cellular metabolism, particularly in the context of mitochondrial function and newly found sulfur metabolism.

DOI: https://doi.org/10.1111/bph.16246
Cell Rep. 2023 Sep 07. pii: S2211-1247(23)01034-3. [Epub ahead of print]42(9): 113023

MMD collaborates with ACSL4 and MBOAT7 to promote polyunsaturated phosphatidylinositol remodeling and susceptibility to ferroptosis.

Vaishnavi V Phadnis, Jamie Snider, Venkateshwari Varadharajan, Iyappan Ramachandiran, Amy A Deik, Zon Weng Lai, Tenzin Kunchok, Elinor Ng Eaton, Carolin Sebastiany, Anna Lyakisheva, Kyle D Vaccaro, Juliet Allen, Zhong Yao, Victoria Wong, Betty Geng, Kipp Weiskopf, Clary B Clish, J Mark Brown, Igor Stagljar, Robert A Weinberg, Whitney S Henry.

  Ferroptosis is a form of regulated cell death with roles in degenerative diseases and cancer. Excessive iron-catalyzed peroxidation of membrane phospholipids, especially those containing the polyunsaturated fatty acid arachidonic acid (AA), is central in driving ferroptosis. Here, we reveal that an understudied Golgi-resident scaffold protein, MMD, promotes susceptibility to ferroptosis in ovarian and renal carcinoma cells in an ACSL4- and MBOAT7-dependent manner. Mechanistically, MMD physically interacts with both ACSL4 and MBOAT7, two enzymes that catalyze sequential steps to incorporate AA in phosphatidylinositol (PI) lipids. Thus, MMD increases the flux of AA into PI, resulting in heightened cellular levels of AA-PI and other AA-containing phospholipid species. This molecular mechanism points to a pro-ferroptotic role for MBOAT7 and AA-PI, with potential therapeutic implications, and reveals that MMD is an important regulator of cellular lipid metabolism.

Keywords:  ACSL4; CP: Cell biology; MBOAT7; MMD; arachidonic acid; cancer; ferroptosis; lipid metabolism; phosphatidylinositol; polyunsaturated fatty acid; scaffold

DOI:  https://doi.org/10.1016/j.celrep.2023.113023
Nature. 2023 Sep 13.

Clustering-predicted structures at the scale of the known protein universe.

Inigo Barrio-Hernandez, Jingi Yeo, Jürgen Jänes, Milot Mirdita, Cameron L M Gilchrist, Tanita Wein, Mihaly Varadi, Sameer Velankar, Pedro Beltrao, Martin Steinegger.

Proteins are key to all cellular processes and their structure is important in understanding their function and evolution. Sequence-based predictions of protein structures have increased in accuracy1, and over 214 million predicted structures are available in the AlphaFold database2. However, studying protein structures at this scale requires highly efficient methods. Here, we developed a structural-alignment-based clustering algorithm-Foldseek cluster-that can cluster hundreds of millions of structures. Using this method, we have clustered all of the structures in the AlphaFold database, identifying 2.30 million non-singleton structural clusters, of which 31% lack annotations representing probable previously undescribed structures. Clusters without annotation tend to have few representatives covering only 4% of all proteins in the AlphaFold database. Evolutionary analysis suggests that most clusters are ancient in origin but 4% seem to be species specific, representing lower-quality predictions or examples of de novo gene birth. We also show how structural comparisons can be used to predict domain families and their relationships, identifying examples of remote structural similarity. On the basis of these analyses, we identify several examples of human immune-related proteins with putative remote homology in prokaryotic species, illustrating the value of this resource for studying protein function and evolution across the tree of life.

DOI: https://doi.org/10.1038/s41586-023-06510-w