Biology subjects

Vimont, E.

Publications and source records attributed to Vimont, E..

6 recordsLinked to original sources

bioRxiv2026

SARS-CoV-2 ORF9b exploits mitochondrial recruitment to TOMM70 for proteasomal protection and tunes inflammatory remodeling during lung infection

Mitochondrial outer membrane proteins are exploited by diverse intracellular pathogens, to modulate cell metabolism and innate sensing pathways. Here, we demonstrate that TOMM70-dependent mitochondrial recruitment is required to protect SARS-CoV-2 ORF9b from proteasomal degradation, a dependency conserved across ORF9b homologs from related coronaviruses. ORF9b mitochondrial recruitment requires the E477 residue of TOMM70, a surface distinct from that used by the parasite Toxoplasma gondii to engage host mitochondria. We further show that TOMM70 is not a passive scaffold: its depletion activates interferon-stimulated gene expression independently of infection and remodels host immunity distinctly from ORF9b, establishing the receptor and viral protein as mechanistically separable. Using ORF9b-deficient SARS-CoV-2, we demonstrate that ORF9b is dispensable for viral replication and pathological responses in human respiratory epithelial cells and lungs of infected golden Syrian hamsters. Omics profiling of SARS-CoV-2 infected lungs revealed an induction of pathways related to COVID-19 in the absence of ORF9b. Notably, ORF9b-deficient virus-infected lungs show elevated expression of C15ORF48, a nuclear-encoded mitochondrial protein that substitutes for Complex IV subunit NDUFA4 to attenuate inflammation. Collectively, we propose that ORF9b is a receptor-gated viral protein whose principal measurable consequence during authentic infection is a restraint on inflammatory respiratory-chain remodeling.

cell biology↗

bioRxiv2025

Mutant CHCHD10 disrupts cytochrome c oxidation and activates retrograde signaling in a model of cardiomyopathy.

Mutations in CHCHD10, a mitochondrial intermembrane space (IMS) protein implicated in proteostasis and cristae maintenance, cause multi-systemic mitochondrial disease. Heterozygous Chchd10 knock-in mice modeling the human CHCHD10S59L variant associated with Amyotrophic Lateral Sclerosis and Frontotemporal Dementia (ALS-FTD) develop a mitochondrial cardiomyopathy driven by CHCHD10 insolubility and aggregation, which is associated with chronic activation of the mitochondrial integrated stress response (mtISR). Here, we demonstrate that cardiac dysfunction in Chchd10S55L/+ mice carrying the orthologous pathogenic variant is associated with dual defects originating at the onset of disease: (1) early bioenergetic dysfunction linked to defects in the mitochondrial copper homeostasis and the oxidation of cytochrome c and (2) maladaptive mtISR signaling via the OMA1-DELE1-HRI axis. Using Oma1E324Q/E324Qknock-in mice, we show that the catalytic inactivation of the mitochondrial protease OMA1 in Chchd10S55L/+ mice delays cardiomyopathy onset without rescuing CHCHD10 insolubility, proteomic remodeling, cristae defects or OXPHOS impairment, demonstrating that mtISR can be uncoupled from the bioenergetic collapse triggered by mutant CHCHD10. Proteomic profiling of soluble and insoluble mitochondrial proteins in Chchd10S55L/+ mice reveals wide-spread disruptions of mitochondrial proteostasis, including IMS proteins involved in cytochrome c biogenesis. Defective respiration in mutant mitochondria could be rescued by the exogenous addition of cytochrome c, pinpointing IMS proteostasis disruption as a key pathogenic mechanism. Our work reveals that mutant CHCHD10 insolubility compromises metabolic resilience by impairing both mitochondrial bioenergetics and stress adaptation, offering new perspectives for the development of therapeutic targets.

cell biology↗

bioRxiv2024

Myocardial disarray drives metabolic inefficiency in human cardiomyocytes

Adult cardiomyocytes are embedded within a highly organized myocardial microenvironment that imposes critical geometric cues essential for the alignment and distribution of organelles and the shaping of their unique, rectangular cellular morphology. Despite the association of cardiomyocyte disarray with human heart disease, the functional consequences of this cellular disorganization remain poorly understood. Here, we leveraged micropatterned substrates to promote structural alignment in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), contrasting the effects of mechanical alignment on mitochondrial form and function with hiPSC-CMs cultured under standard unconstrained conditions. Cardiomyocytes cultured under unconstrained conditions exhibited misaligned sarcomeres and a perinuclear mitochondrial distribution while micropatterned hiPSC-CMs developed linear myofibrils and reconfigured sarcomere and mitochondrial organization, which increased mitochondrial respiration without augmenting mitochondrial mass. Notably, micropatterned hiPSC-CMs exhibited an increased number of mitochondrial-associated membranes, as determined by proximity ligation assays and transmission electron microscopy, suggesting enhanced interactions between the sarcoplasmic reticulum and mitochondria. Together, these findings demonstrate that mitochondrial-sarcoplasmic architecture and geometry are critical spatial features that ensure bioenergetic efficiency of cardiomyocytes. This work underscores the importance of cellular organization in cardiomyocyte metabolism and function, providing insights into the pathophysiology of cardiac diseases marked by cellular disarray.

cell biology↗

bioRxiv2023

Mtfp1 ablation enhances mitochondrial respiration and protects against hepatic steatosis

Hepatic steatosis is the result of an imbalance between nutrient delivery and metabolism in the liver. It is the first hallmark of Non-alcoholic fatty liver disease (NAFLD) and is characterized by the accumulation of excess lipids in the liver that can drive liver failure, inflammation, and cancer. Mitochondria control the fate and function of cells and compelling evidence implicates these multifunctional organelles in the appearance and progression of liver dysfunction, although it remains to be elucidated which specific mitochondrial functions are actually causally linked to NAFLD. Here, we identified Mitochondrial Fission Process 1 protein (MTFP1) as a key regulator of mitochondrial and metabolic activity in the liver. Deletion of Mtfp1 in hepatocytes is physiologically benign in mice yet leads to the upregulation of oxidative phosphorylation (OXPHOS) activity and mitochondrial respiration, independently of mitochondrial biogenesis. Consequently, hepatocyte-specific knockout mice are protected against high fat diet-induced hepatic steatosis and metabolic dysregulation. Additionally, we find that deletion of Mtfp1 in liver mitochondria inhibits mitochondrial permeability transition pore opening in hepatocytes, conferring protection against apoptotic liver damage in vivo and ex vivo. Our work uncovers novel functions of MTFP1 in the liver, positioning this gene as an unexpected regulator of OXPHOS and a therapeutic candidate for NAFLD.

physiology↗

bioRxiv2021

Mitochondrial fission process 1 (MTFP1) controls bioenergetic efficiency and prevents inflammatory cardiomyopathy and heart failure in mice

Mitochondria are paramount to the metabolism and survival of cardiomyocytes. Here we show that Mitochondrial Fission Process 1 (MTFP1) is essential for cardiac structure and function. Constitutive knockout of cardiomyocyte MTFP1 in mice resulted in adult-onset dilated cardiomyopathy (DCM) characterized by sterile inflammation and cardiac fibrosis that progressed to heart failure and middle-aged death. Failing hearts from cardiomyocyte-restricted knockout mice displayed a general decline in mitochondrial gene expression and oxidative phosphorylation (OXPHOS) activity. Pre-DCM, we observed no defects in mitochondrial morphology, content, gene expression, OXPHOS assembly nor phosphorylation dependent respiration. However, knockout cardiac mitochondria displayed reduced membrane potential and increased non-phosphorylation dependent respiration, which could be rescued by pharmacological inhibition of the adenine nucleotide translocase ANT. Primary cardiomyocytes from pre-symptomatic knockout mice exhibited normal excitation-contraction coupling but increased sensitivity to programmed cell death (PCD), which was accompanied by an opening of the mitochondrial permeability transition pore (mPTP). Intriguingly, mouse embryonic fibroblasts deleted for Mtfp1 recapitulated PCD sensitivity and mPTP opening, both of which could be rescued by pharmacological or genetic inhibition of the mPTP regulator Cyclophilin D. Collectively, our data demonstrate that contrary to previous in vitro studies, the loss of the MTFP1 promotes mitochondrial uncoupling and increases cell death sensitivity, causally mediating pathogenic cardiac remodeling.

physiology↗

bioRxiv2021

High-throughput phenotypic screen for genetic modifiers in patient-derived OPA1 mutant fibroblasts identifies PGS1 as a functional suppressor of mitochondrial fragmentation

Mutations affecting the mitochondrial fusion protein Optic Atrophy 1 (OPA1) cause autosomal dominant optic atrophy (DOA) - one of the most common form of mitochondrial disease. The majority of patients develop isolated optic atrophy, but about 20% of OPA1 mutation carriers manifest more severe neurological deficits as part of a "DOA+" phenotype. OPA1 deficiency causes mitochondrial fragmentation and also disrupts cristae organization, oxidative phosphorylation, mitochondrial DNA (mtDNA) maintenance, and cell viability. It has not yet been established whether phenotypic severity can be modulated by genetic modifiers of OPA1. To better understand the genetic regulation of mitochondrial dynamics, we established a high-throughput imaging pipeline using supervised machine learning (ML) to perform unbiased, quantitative mitochondrial morphology analysis that was coupled with a bespoke siRNA library targeting the entire known mitochondrial proteome (1531 genes), providing a detailed phenotypic screening of human fibroblasts. In control fibroblasts, we identified known and novel genes whose depletion promoted elongation or fragmentation of the mitochondrial network. In DOA+ patient fibroblasts, we identified 91 candidate genes whose depletion prevents mitochondrial fragmentation, including the mitochondrial fission genes DNM1L, MIEF1, and SLC25A46, but also genes not previously linked to mitochondrial dynamics such as Phosphatidyl Glycerophosphate Synthase (PGS1), which belongs to the cardiolipin (CL) synthesis pathway. PGS1 depletion reduces CL content in mitochondria and rebalances mitochondrial dynamics in OPA1-deficient fibroblasts by inhibiting mitochondrial fission, which improves defective respiration, but does not rescue mtDNA depletion, cristae dysmorphology or apoptotic sensitivity. Our data reveal that the multifaceted roles of OPA1 in mitochondria can be functionally uncoupled by modulating mitochondrial lipid metabolism, providing novel insights into the cellular relevance of mitochondrial fragmentation. This study illustrates the power of a first-in-kind objective automated imaging approach to uncover genetic modifiers of mitochondrial disease through high-throughput phenotypic screening of patient fibroblasts.

cell biology↗