Biology subjects

Molinie, T.

Publications and source records attributed to Molinie, T..

4 recordsLinked to original sources

bioRxiv2025

Stress adaptation of mitochondrial protein import by OMA1-mediated degradation of DNAJC15

Mitochondria adapt to cellular stress to ensure cell survival. The stress-regulated mitochondrial peptidase OMA1 orchestrates these adaptive responses, which limit mitochondrial fusion and promote mitochondrial stress signaling and metabolic rewiring. Here, we show that cellular stress adaptation involves OMA1-mediated regulation of mitochondrial protein import and OXPHOS biogenesis. OMA1 cleaves the mitochondrial chaperone DNAJC15 and promotes its degradation by the m-AAA protease AFG3L2. Loss of DNAJC15 reduces the import of OXPHOS-related proteins via the TIMM23-TIMM17A protein translocase, limiting OXPHOS biogenesis under conditions of mitochondrial dysfunction. Non-imported mitochondrial preproteins accumulate at the endoplasmic reticulum and induce an ATF6-related unfolded protein response. Our results demonstrate stress-dependent changes in protein import specificity as part of the OMA1-mediated mitochondrial stress response and highlight the interdependence of proteostasis regulation between different organelles.

cell biology↗

bioRxiv2023

Preserved respiratory chain capacity and physiology in mice with profoundly reduced levels of mitochondrial respirasomes

The mammalian respiratory chain complexes I, III2 and IV (CI, CIII2 and CIV) are critical for cellular bioenergetics and form a stable assembly, the respirasome (CI- CIII2-CIV), that is biochemically and structurally well documented. The role of the respirasome in bioenergetics and regulation of metabolism is subject to intense debate and is difficult to study because the individual respiratory chain complexes coexist together with high levels of respirasomes. To critically investigate the in vivo role of the respirasome, we generated homozygous knock-in mice that have normal levels of respiratory chain complexes but profoundly decreased levels of respirasomes. Surprisingly, the mutant mice are healthy, with preserved respiratory chain capacity and normal exercise performance. Our findings show that high levels of respirasomes are dispensable for maintaining bioenergetics and physiology in the mouse, but raises questions about their alternate functions, such as relating to regulation of protein stability and prevention of age-associated protein aggregation.

molecular biology↗

bioRxiv2023

MitoMouse is a model reconstruction of murine mitochondrial metabolism

Mitochondria, apart from being the powerhouses of our cells, are key players in cellular metabolism and homeostasis. As a consequence, the core bioenergetics and metabolism of mitochondria are well studied considering the role that dysregulated mitochondrial metabolism plays in disease. Flux Balance Analysis, used in conjunction with metabolic model reconstructions is a powerful computational tool that predicts metabolism. The resulting quantitative descriptions of metabolic dysregulation not only allows current hypotheses to be tested in silico, but can also lead to novel model driven hypotheses that can be experimentally verified. Several metabolic reconstructions for human and mouse metabolism exist, but no model specific to mouse mitochondrial metabolism exists. Here, we have created a mouse-specific mitochondrial metabolic model, mitoMouse, which is based on the high-quality human MitoCore mode. MitoMouse contains 390 genes and 445 metabolites involved in 560 unique reactions, is able to model central carbon metabolism and has been extended to contain reduction of the CoQ complex of Oxidative Phosphorylation by the enzyme DHODH. MitoMOuse was validated to accurately model the important metabolic switch involving CoQ reduction resulting from increased malate import, as recently shown in mouse cardiac tissue. We expect this model to be of immense interest and relevance to researchers working on murine mitochondrial metabolism.

systems biology↗

bioRxiv2021

MDH2 is a metabolic switch rewiring the fuelling of respiratory chain and TCA cycle

The mitochondrial respiratory chain (RC) enables many metabolic processes by regenerating both mitochondrial and cytosolic NAD+ and ATP. The oxidation by the RC of the NADH metabolically produced in the cytosol involves redox shuttles as the malate-aspartate shuttle (MAS) and is of paramount importance for cell fate. However, the specific metabolic regulations allowing mitochondrial respiration to prioritize NADH oxidation in response to high NADH/NAD+ redox stress have not been elucidated. Our work demonstrates the crucial role played by MDH2 in orchestrating the electron fuelling of the RC. On one hand, MDH2 mediated oxaloacetate (OAA) production allows mitochondria to metabolize pyruvate and glutamate and to feed complex I with NADH, whereas on the other hand, OAA inhibits complex II. This regulatory mechanism synergistically increases RCs NADH oxidative capacity and rewires MDH2 driven anaplerosis of the TCA favouring the oxidation of malate produced by the MAS.

biochemistry↗