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LONP-1 deficiency causes dysregulated protein synthesis within mitochondria that is restored by mitoribosomal mutations

ABSTRACT: Mitochondrial homeostasis is maintained by multiple molecular chaperones and proteases located within the organelle. The mitochondrial matrix-localized protease LONP-1 degrades oxidatively damaged or misfolded proteins. Importantly, LONP-1 also regulates mitochondrial DNA replication. Here, we show that mutations in C. elegans that impair LONP-1 function cause dysregulation of mitochondrial DNA replication, mitochondrial RNA transcription and protein synthesis within the mitochondrial matrix. LONP-1 deficient worms had reduced levels of oxidative phosphorylation proteins despite increased mt-DNA encoded protein synthesis. Via a forward genetic screen, we identified three mutations that restored mitochondrial function and the rate of development in lonp-1 mutants to levels comparable to those in wildtype worms. Interestingly, all three suppressor mutations were found in genes encoding mitochondrial ribosome proteins. A point mutation in the small mitochondrial ribosome protein MRPS-38 restored oxidative phosphorylation in lonp-1 mutant worms. Combined, our results suggest that LONP-1 regulates mitochondrial protein synthesis and that the suppressor mutations within MRPS-38 or MRPS-15 enhance oxidative phosphorylation complex assembly by slowing translation.

ORGANISM(S): Caenorhabditis elegans

PROVIDER: GSE315983 | GEO | 2026/01/09

REPOSITORIES: GEO

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Project description:The mitochondrial unfolded protein response (UPR mt ) is regulated by the bZIP protein ATFS-1 which promotes mitochondrial protein homeostasis (proteostasis) and mitochondrial biogenesis in Caenorhabditis elegans . Upon mitochondrial perturbation, the ATFS-1-dependent transcriptional program promotes gene expression, leading to mitochondrial recovery. Conversely, atfs-1 -deletion worms harbor dysfunctional mitochondria, are developmentally impaired, and short-lived. However, atfs-1 -deletion worms develop to adults suggesting the presence of other signaling pathways that promote mitochondrial function and biogenesis in the absence of atfs-1 . We hypothesized that additional transcription factors regulate, or promote, mitochondrial function in the absence of atfs-1 . Here, we screened for transcription factors that could reduce the decline in mitochondrial function in the atfs-1 mutants when inhibited. Here, we demonstrate that inhibition of the nuclear hormone receptor NHR-180 re-establishes a functional mitochondrial network in atfs-1(null) worms, increases mtDNA content, and improves the developmental rate of wildtype worms. NHR-180 increases transcription of genes required for cytosolic protein synthesis in response to mitochondrial perturbation. Inhibition of the S6 kinase homolog, rsks-1 , in atfs-1(null) worms leads to a recovery of the mitochondrial network and mtDNA content consistent with nhr-180 regulating expression of protein synthesis components. Consistent with the observations in C. elegans , S6 kinase inhibition also increased mitochondrial biogenesis in mammalian atf5 -knockout cells that harbor severely impaired mitochondria. Intriguingly, nhr-180 or S6 kinase inhibition also rescues mitochondrial dysfunction caused by mutations in multiple genes required for oxidative phosphorylation. Combined, these studies suggest that increased protein synthesis contributes to the mitochondrial dysfunction caused by perturbations in OXPHOS gene expression and suggest a relatively straightforward approach to reducing the impact of mitochondrial dysfunction.

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LONP-1 deficiency causes dysregulated protein synthesis within mitochondria that is restored by mitoribosomal mutations

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