bims-mitpro 2025-02-23 papers

Issue of 2025–02–23
four papers selected by
Andreas Kohler, Umeå University

bioRxiv. 2025 Feb 05. pii: 2025.02.03.636310. [Epub ahead of print]

Loss of an uncharacterized mitochondrial methionine tRNA-synthetase induces mitochondrial unfolded protein response in Caenorhabditis elegans.

Bharat Vivan Thapa, Mohit Das, James P Held, Maulik R Patel.

Aminoacyl-tRNA synthetases (aaRSs) are essential for translation, as they charge tRNA molecules with their corresponding amino acids. Alterations in aaRSs can significantly disrupt both cytosolic and mitochondrial translation. Through a forward genetic screen for mitochondrial unfolded protein response (UPR mt ) activators in C. elegans , we identified a missense mutation (P447V) in the previously uncharacterized gene Y105E8A.20, which encodes a dually localized methionine tRNA synthetase (MetRS). Here, we characterize the UPR mt induction by Y105E8A.20, which we call mars-2 , and demonstrate that the P447V allele is a loss-of-function mutation. Furthermore, we show impaired mars-2 activity in the mitochondria triggers UPR mt . This strain provides a valuable tool for studying mitochondrial translation and understanding how aaRSs are involved in mitochondrial homeostasis.

DOI: https://doi.org/10.1101/2025.02.03.636310

G3 (Bethesda). 2025 Feb 17. pii: jkaf023. [Epub ahead of print]

VPS13D mutations affect mitochondrial homeostasis and locomotion in Caenorhabditis elegans.

Xiaomeng Yin, Ruoxi Wang, Andrea Thackeray, Eric H Baehrecke, Mark J Alkema.

Mitochondria control cellular metabolism, serve as hubs for signaling and organelle communication, and are important for the health and survival of cells. VPS13D encodes a cytoplasmic lipid transfer protein that regulates mitochondrial morphology, mitochondria and endoplasmic reticulum (ER) contact, quality control of mitochondria. VPS13D mutations have been reported in patients displaying ataxic and spastic gait disorders with variable age of onset. Here we used CRISPR/Cas9 gene editing to create VPS13D related-spinocerebellar ataxia-4 (SCAR4) missense mutations and C-terminal deletion in VPS13D's orthologue vps-13D in C. elegans. Consistent with SCAR4 patient movement disorders and mitochondrial dysfunction, vps-13D mutant worms exhibit locomotion defects and abnormal mitochondrial morphology. Importantly, animals with a vps-13D deletion or a N3017I missense mutation exhibited an increase in mitochondrial unfolded protein response (UPRmt). The cellular and behavioral changes caused by VPS13D mutations in C. elegans advance the development of animal models that are needed to study SCAR4 pathogenesis.

Keywords: Caenorhabditis elegans ; VPS13D ; vps-13D ; WormBase; mitochondrial homeostasis

DOI: https://doi.org/10.1093/g3journal/jkaf023

bioRxiv. 2025 Jan 30. pii: 2025.01.30.635785. [Epub ahead of print]

Mdm38/LETM1 couples ion homeostasis and proteostatic mechanisms in the inner mitochondrial membrane.

Iryna Bohovych, Gabriella Menezes da Silva, Saieeda Fabia Ali, Emma J Bergmeyer, Edward M Germany, Adarsh Mayank, James A Wohlschlegel, Jason C Casler, Muhammad Arifur Rahman, Taras Y Nazarko, Maureen Tarsio, Takuya Shiota, Laura L Lackner, Steven M Claypool, Patricia M Kane, Antoni Barrientos, Oleh Khalimonchuk.

The mitochondrial inner membrane is among the most protein-dense cellular membranes. Its functional integrity is maintained through a concerted action of several conserved mechanisms that are far from clear. Here, using the baker's yeast model, we functionally characterize Mdm38/LETM1, a disease-related protein implicated in mitochondrial translation and ion homeostasis, although the molecular basis of these connections remains elusive. Our findings reveal a novel role for Mdm38 in maintaining protein homeostasis within the inner membrane. Specifically, we demonstrate that Mdm38 is required for mitochondrial iron homeostasis and for signaling iron bioavailability from mitochondria to vacuoles. These processes are linked to the m- AAA quality control protease, whose unrestrained activity disrupts the assembly and stability of respiratory chain complexes in Mdm38-deficient cells. Our study highlights the central role of Mdm38 in mitochondrial biology and reveals how it couples proteostatic mechanisms to ion homeostasis across subcellular compartments.

DOI: https://doi.org/10.1101/2025.01.30.635785

bioRxiv. 2025 Feb 03. pii: 2025.02.01.636045. [Epub ahead of print]

Mitophagy at the oocyte-to-zygote transition promotes species immortality.

Siddharthan Balachandar Thendral, Sasha Bacot, Katherine S Morton, Qiuyi Chi, Isabel W Kenny-Ganzert, Joel N Meyer, David R Sherwood.

The quality of inherited mitochondria determines embryonic viability 1 , metabolic health during adulthood and future generation endurance. The oocyte is the source of all zygotic mitochondria 2 , and mitochondrial health is under strict developmental regulation during early oogenesis 3-5 . Yet, fully developed oocytes exhibit the presence of deleterious mitochondrial DNA (mtDNA) 6,7 and mitochondrial dysfunction from high levels of endogenous reactive oxygen species 8 and exogenous toxicants 9 . How fully developed oocytes prevent transmission of damaged mitochondria to the zygotes is unknown. Here we discover that the onset of oocyte-to-zygote transition (OZT) developmentally triggers a robust and rapid mitophagy event that we term mitophagy at OZT (MOZT). We show that MOZT requires mitochondrial fragmentation, activation of the macroautophagy system and the mitophagy receptor FUNDC1, but not the prevalent mitophagy factors PINK1 and BNIP3. Oocytes upregulate expression of FUNDC1 in response to diverse mitochondrial insults, including mtDNA mutations and damage, uncoupling stress, and mitochondrial dysfunction, thereby promoting selection against damaged mitochondria. Loss of MOZT leads to increased inheritance of deleterious mtDNA and impaired bioenergetic health in the progeny, resulting in diminished embryonic viability and the extinction of descendent populations. Our findings reveal FUNDC1-mediated MOZT as a mechanism that preserves mitochondrial health during the mother-to-offspring transmission and promotes species continuity. These results may explain how mature oocytes from many species harboring mutant mtDNA give rise to healthy embryos with reduced deleterious mtDNA.

DOI: https://doi.org/10.1101/2025.02.01.636045