Biology subjects

Rugarli, E.

Publications and source records attributed to Rugarli, E..

5 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↗

bioRxiv2024

Pathogenesis of mtDNA point mutation m.10191T>C affecting complex I function is a multifactorial process leading to metabolic remodeling of mitochondria

Inherited mitochondrial disorders are of multiple genetic origins and may lead to a broad range of frequently severe disease phenotypes. Yet, the correlation between molecular causes and clinical presentations is poorly understood. To address this conundrum, we thoroughly investigated the consequences of the well-known pathogenic mitochondrial DNA mutation m.10191T>C. The mutation changes serine-45 in subunit ND3 of respiratory chain complex I to proline and causes Leigh syndrome, which is one of the most devastating mitochondrial diseases. Human mitochondria carrying the mutation ND3S45P retained 30-40% of complex I activity and oxidative phosphorylation capacity. In stark contrast, intact mutant cells exhibited only minimal oxygen consumption and a massively increased NADH/NAD+ ratio. Since the energy barrier for the Active/Deactive transition of complex I was reduced by [~]20 kJ{middle dot}mol-1 in mutant cells, we concluded that complex I was shut-off by malfunctioning of an as yet unknown regulatory pathway. Comprehensive analysis of the mitochondrial complexome of cybrids, patient fibroblasts and muscle biopsies rendered other causes for the accumulation of NADH unlikely. The complexome datasets provide a rich resource for further studies to discover possible additional factors involved in regulating complex I. We propose that the derailed regulation of complex I is the main culprit leading to NADH accumulation and eventually the severity of the disease phenotype caused by mutation ND3S45P.

biochemistry↗

bioRxiv2024

AFG3L2-mediated proteolysis restricts mitochondrial biogenesis and gene expression in hypoxia

Mitochondria are metabolically rewired in hypoxia when cells switch to glycolytic growth. In addition to the well-established role of transcriptional and translational programs, there is increasing evidence that post-translational mechanisms contribute to the rapid adaptation of the mitochondrial proteome to hypoxia. Here, we have used a proteomic survey to define how the m-AAA protease AFG3L2, a proteolytic complex in the inner mitochondrial membrane, regulates mitochondrial proteostasis. Our experiments identify a broad spectrum of mitochondrial substrate proteins and show that AFG3L2 is activated in hypoxia along an HIF1-mTORC1 signaling axis. AFG3L2-mediated proteolysis restricts mitochondrial biogenesis and gene expression by degrading proteins, which are involved in mitochondrial protein import, mitochondrial transcription, mRNA processing, mRNA modification and stability, and RNA granule formation. Our experiments highlight the important contribution of proteolytic rewiring of the mitochondrial proteome for the adaptation to low oxygen tension and shed new light on the pathophysiology of several neurodegenerative disorders associated with mutations in AFG3L2.

cell biology↗

bioRxiv2023

CLUH maintains functional mitochondria and translation in motoneuronal axons and prevents peripheral neuropathy

Transport and local translation of mRNAs in distal axonal compartments are essential for neuronal viability. Local synthesis of nuclear-encoded mitochondrial proteins protects mitochondria from damage during their long journey along the axon, however the regulatory factors involved are largely unknown. Here, we show that CLUH, a cytosolic protein that binds mRNAs encoding mitochondrial proteins, is essential for preventing axonal degeneration of spinal motoneurons and maintaining motor behavior in the mouse. We demonstrate that CLUH is enriched in the growth cone of developing spinal motoneurons and is required for their growth. The absence of CLUH affects the abundance of target mRNAs and the corresponding mitochondrial proteins more prominently in axons, leading to ATP deficits specifically in the growth cone. CLUH binds ribosomal subunits, translation initiation and ribosome recycling components, and preserves axonal translation. Overexpression of the ribosome recycling factor ABCE1 rescues the growth cone and translation defects in CLUH-deficient motoneurons. In conclusion, we demonstrate a role for CLUH in mitochondrial quality control and translational regulation in axons, which are essential for their development and long-term integrity and function.

cell biology↗

bioRxiv2020

The mammalian CLU homolog FMT controls development and behavior in Arabidopsis

Mitochondria in animals are associated with development, as well as physiological and pathological behaviors. Several conserved mitochondrial genes exist between plants and higher eukaryotes. Yet, comparative mitochondrial function among plant and animal species is poorly understood. Here, we show that FMT (FRIENDLY MITOCHONDRIA) from Arabidopsis thaliana, a highly conserved homolog of the mammalian CLU (CLUSTERED MITOCHONDRIA) gene family encoding mitochondrial proteins associated with developmental alterations and adult physiological and pathological behaviors, affects whole plant morphology and development under salt stress and control conditions. FMT was found to regulate mitochondrial morphology and dynamics as well as germination, root length, and flowering time. Here, we show that it also affects leaf expansion growth, salt stress-responses and hyponasty. Strikingly, FMT impacted the speed of hyponasty with corresponding change in speed of locomotion of CLU heterozygous knockout mice. These observations indicate that homologous genes affect homologous functions in plants and animals offering the possibility to develop plant models for the study of mammalian behaviors.

plant biology↗