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EOLA1, a novel mitochondria-localized protein critical for heart functions via regulating mitochondrial translation

ABSTRACT: This project aims to explore the molecular mechanisms underlying mitochondrial dysfunction caused by the depletion of EOLA1, a novel mitochondria-localized protein. By employing a combination of molecular and biochemical assays, we have identified the EOLA1-interacting partners using affinity purification coupled with high-performance liquid chromatography-mass spectrometry (HPLC-MS). Notably, over 40% of these interacting proteins are mitochondrial, aligning with EOLA1's exclusive mitochondrial localization. Among these, 20 components of mitochondrial ribosomal small subunits (mt-SSUs) were identified, in contrast to only 2 components from mitochondrial ribosomal large subunits (mt-LSUs), among 100 mitochondrial proteins that may interact with EOLA1. This finding is consistent with the potential role of EOLA1 in mitochondrial translation11. Additionally, mitochondrial Tu translation elongation factor (TUFM), involved in mitochondrial protein translation, was identified in this complex. The interaction with TUFM was validated by western blotting and through endogenous coimmunoprecipitation experiments. This project seeks to elucidate the role of EOLA1 in mitochondrial function and its implications in health and disease.

ORGANISM(S): Homo Sapiens

SUBMITTER: Hao Chen

PROVIDER: PXD066586 | iProX | Fri Jul 25 00:00:00 GMT+01:00 2025

REPOSITORIES: iProX

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Project description:The interplay between ribosomal protein composition and mitochondrial function is essential for sustaining energy homeostasis. Precise stoichiometric production of ribosomal proteins is crucial to maximize protein synthesis efficiency while reducing the energy costs to the cell. However, the impact of this balance on mitochondrial ATP generation, morphology and function remains unclear. Particularly, the loss of a single copy ribosomal protein gene is observed in Mendelian disorders like Diamond Blackfan Anemia and is common in somatic tumors, yet the implications of this imbalance on mitochondrial function and energy dynamics are still unclear. In this study, we investigated the impact of haploinsufficiency for four ribosomal protein genes implicated in ribosomopathy disorders (rps-10, rpl-5, rpl-33, rps-23) in Caenorhabditis elegans and corresponding reductions in human lymphoblast cells. Our findings uncover significant, albeit variably penetrant, mitochondrial morphological differences across these mutants, alongside an upregulation of glutathione transferases, and SKN-1 dependent increase in oxidative stress resistance, indicative of increased ROS production. Specifically, loss of a single copy of rps-10 in C. elegans led to decreased mitochondrial activity, characterized by lower energy levels and reduced oxygen consumption. A similar reduction in mitochondrial activity and energy levels was observed in human leukemia cells with a 50% reduction in RPS10 transcript levels. Importantly, we also observed alterations in the translation efficiency of nuclear and mitochondrial electron transport chain components in response to reductions in ribosomal protein genes’ expression in both C. elegans and human cells. This suggests a conserved mechanism whereby the synthesis of components vital for mitochondrial function are adjusted in the face of compromised ribosomal machinery. Finally, mitochondrial membrane and cytosolic ribosomal components exhibited significant covariation at the RNA and translation efficiency level in lymphoblastoid cells across a diverse group of individuals, emphasizing the interplay between the protein synthesis machinery and mitochondrial energy production. By uncovering the impact of ribosomal protein haploinsufficiency on the translation efficiency of electron transport chain components, mitochondrial physiology, and the adaptive stress responses, we provide evidence for an evolutionarily conserved strategy to safeguard cellular functionality under genetic stress.

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EOLA1, a novel mitochondria-localized protein critical for heart functions via regulating mitochondrial translation

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