bims-mitpro 2024-10-13 papers

Issue of 2024–10–13
three papers selected by
Andreas Kohler, Umeå University

Nat Commun. 2024 Oct 08. 15(1): 8723

A germline-to-soma signal triggers an age-related decline of mitochondrial stress response.

Liankui Zhou, Liu Jiang, Lan Li, Chengchuan Ma, Peixue Xia, Wanqiu Ding, Ying Liu.

The abilities of an organism to cope with extrinsic stresses and activate cellular stress responses decline during aging. The signals that modulate stress responses in aged animals remain to be elucidated. Here, we discover that feeding Caenorhabditis elegans (C. elegans) embryo lysates to adult worms enabled the animals to activate the mitochondrial unfolded protein response (UPRmt) upon mitochondrial perturbations. This discovery led to subsequent investigations that unveil a hedgehog-like signal that is transmitted from the germline to the soma in adults to inhibit UPRmt in somatic tissues. Additionally, we find that the levels of germline-expressed piRNAs in adult animals markedly decreased. This reduction in piRNA levels coincides with the production and secretion of a hedgehog-like signal and suppression of the UPRmt in somatic cells. Building upon existing research, our study further elucidates the intricate mechanisms of germline-to-soma signaling and its role in modulating the trade-offs between reproduction and somatic maintenance within the context of organismal aging.

DOI: https://doi.org/10.1038/s41467-024-53064-0

EMBO J. 2024 Oct 08.

DELE1 maintains muscle proteostasis to promote growth and survival in mitochondrial myopathy.

Hsin-Pin Lin, Jennifer D Petersen, Alexandra J Gilsrud, Angelo Madruga, Theresa M D'Silva, Xiaoping Huang, Mario K Shammas, Nicholas P Randolph, Kory R Johnson, Yan Li, Drew R Jones, Michael E Pacold, Derek P Narendra.

Mitochondrial dysfunction causes devastating disorders, including mitochondrial myopathy, but how muscle senses and adapts to mitochondrial dysfunction is not well understood. Here, we used diverse mouse models of mitochondrial myopathy to show that the signal for mitochondrial dysfunction originates within mitochondria. The mitochondrial proteins OMA1 and DELE1 sensed disruption of the inner mitochondrial membrane and, in response, activated the mitochondrial integrated stress response (mt-ISR) to increase the building blocks for protein synthesis. In the absence of the mt-ISR, protein synthesis in muscle was dysregulated causing protein misfolding, and mice with early-onset mitochondrial myopathy failed to grow and survive. The mt-ISR was similar following disruptions in mtDNA maintenance (Tfam knockout) and mitochondrial protein misfolding (CHCHD10 G58R and S59L knockin) but heterogenous among mitochondria-rich tissues, with broad gene expression changes observed in heart and skeletal muscle and limited changes observed in liver and brown adipose tissue. Taken together, our findings identify that the DELE1 mt-ISR mediates a similar response to diverse forms of mitochondrial stress and is critical for maintaining growth and survival in early-onset mitochondrial myopathy.

Keywords: Mitochondria Unfolded Protein Response (mt-UPR); Mitochondrial Disorders; Mitohormesis; Mitonuclear Communication; Mitophagy

DOI: https://doi.org/10.1038/s44318-024-00242-x

Nat Commun. 2024 Oct 08. 15(1): 8666

Ribosomes hibernate on mitochondria during cellular stress.

Olivier Gemin, Maciej Gluc, Higor Rosa, Michael Purdy, Moritz Niemann, Yelena Peskova, Simone Mattei, Ahmad Jomaa.

Cell survival under nutrient-deprived conditions relies on cells' ability to adapt their organelles and rewire their metabolic pathways. In yeast, glucose depletion induces a stress response mediated by mitochondrial fragmentation and sequestration of cytosolic ribosomes on mitochondria. This cellular adaptation promotes survival under harsh environmental conditions; however, the underlying mechanism of this response remains unknown. Here, we demonstrate that upon glucose depletion protein synthesis is halted. Cryo-electron microscopy structure of the ribosomes show that they are devoid of both tRNA and mRNA, and a subset of the particles depicted a conformational change in rRNA H69 that could prevent tRNA binding. Our in situ structural analyses reveal that the hibernating ribosomes tether to fragmented mitochondria and establish eukaryotic-specific, higher-order storage structures by assembling into oligomeric arrays on the mitochondrial surface. Notably, we show that hibernating ribosomes exclusively bind to the outer mitochondrial membrane via the small ribosomal subunit during cellular stress. We identify the ribosomal protein Cpc2/RACK1 as the molecule mediating ribosomal tethering to mitochondria. This study unveils the molecular mechanism connecting mitochondrial stress with the shutdown of protein synthesis and broadens our understanding of cellular responses to nutrient scarcity and cell quiescence.

DOI: https://doi.org/10.1038/s41467-024-52911-4