bims-tricox 2024-07-21 papers

Issue of 2024–07–21
three papers selected by
Yash Verma, University of Zurich

Cell Rep. 2024 Jul 17. pii: S2211-1247(24)00802-7. [Epub ahead of print]43(8): 114473

ATAD1 prevents clogging of TOM and damage caused by un-imported mitochondrial proteins.

John Kim, Madeleine Goldstein, Lauren Zecchel, Ryan Ghorayeb, Christopher A Maxwell, Hilla Weidberg.

Mitochondria require the constant import of nuclear-encoded proteins for proper functioning. Impaired protein import not only depletes mitochondria of essential factors but also leads to toxic accumulation of un-imported proteins outside the organelle. Here, we investigate the consequences of impaired mitochondrial protein import in human cells. We demonstrate that un-imported proteins can clog the mitochondrial translocase of the outer membrane (TOM). ATAD1, a mitochondrial ATPase, removes clogged proteins from TOM to clear the entry gate into the mitochondria. ATAD1 interacts with both TOM and stalled proteins, and its knockout results in extensive accumulation of mitochondrial precursors as well as decreased protein import. Increased ATAD1 expression contributes to improved fitness of cells with inefficient mitochondrial protein import. Overall, we demonstrate the importance of the ATAD1 quality control pathway in surveilling protein import and its contribution to cellular health.

Keywords: AAA ATPase; ATAD1; CP: Cell biology; CP: Metabolism; TOM clogging; mitochondrial protein import; mitochondrial stress; protein quality control; proteotoxicity

DOI: https://doi.org/10.1016/j.celrep.2024.114473

iScience. 2024 Jul 19. 27(7): 110185

Supernumerary proteins of the human mitochondrial ribosomal small subunit are integral for assembly and translation.

Taru Hilander, Ryan Awadhpersad, Geoffray Monteuuis, Krystyna L Broda, Max Pohjanpelto, Elizabeth Pyman, Sachin Kumar Singh, Tuula A Nyman, Isabelle Crevel, Robert W Taylor, Ann Saada, Diego Balboa, Brendan J Battersby, Christopher B Jackson, Christopher J Carroll.

Mitochondrial ribosomes (mitoribosomes) have undergone substantial evolutionary structural remodeling accompanied by loss of ribosomal RNA, while acquiring unique protein subunits located on the periphery. We generated CRISPR-mediated knockouts of all 14 unique (mitochondria-specific/supernumerary) human mitoribosomal proteins (snMRPs) in the small subunit to study the effect on mitoribosome assembly and protein synthesis, each leading to a unique mitoribosome assembly defect with variable impact on mitochondrial protein synthesis. Surprisingly, the stability of mS37 was reduced in all our snMRP knockouts of the small and large ribosomal subunits and patient-derived lines with mitoribosome assembly defects. A redox-regulated CX9C motif in mS37 was essential for protein stability, suggesting a potential mechanism to regulate mitochondrial protein synthesis. Together, our findings support a modular assembly of the human mitochondrial small ribosomal subunit mediated by essential supernumerary subunits and identify a redox regulatory role involving mS37 in mitochondrial protein synthesis in health and disease.

Keywords: biochemistry; biological sciences; cell biology; molecular biology

DOI: https://doi.org/10.1016/j.isci.2024.110185

Science. 2024 Jul 19. 385(6706): eadm9238

The human mitochondrial mRNA structurome reveals mechanisms of gene expression.

J Conor Moran, Amir Brivanlou, Michele Brischigliaro, Flavia Fontanesi, Silvi Rouskin, Antoni Barrientos.

The human mitochondrial genome encodes crucial oxidative phosphorylation system proteins, pivotal for aerobic energy transduction. They are translated from nine monocistronic and two bicistronic transcripts whose native structures remain unexplored, posing a gap in understanding mitochondrial gene expression. In this work, we devised the mitochondrial dimethyl sulfate mutational profiling with sequencing (mitoDMS-MaPseq) method and applied detection of RNA folding ensembles using expectation-maximization (DREEM) clustering to unravel the native mitochondrial messenger RNA (mt-mRNA) structurome in wild-type (WT) and leucine-rich pentatricopeptide repeat-containing protein (LRPPRC)-deficient cells. Our findings elucidate LRPPRC's role as a holdase contributing to maintaining mt-mRNA folding and efficient translation. mt-mRNA structural insights in WT mitochondria, coupled with metabolic labeling, unveil potential mRNA-programmed translational pausing and a distinct programmed ribosomal frameshifting mechanism. Our data define a critical layer of mitochondrial gene expression regulation. These mt-mRNA folding maps provide a reference for studying mt-mRNA structures in diverse physiological and pathological contexts.

DOI: https://doi.org/10.1126/science.adm9238