FAM162A is Crucial for Mitochondrial Structure, Dynamics, and Bioenergetics, Driving Cellular Protection and Longevity

IntroductionFAM162A is a mitochondrial protein evolutionarily conserved across taxa and ubiquitously expressed in various tissues. It is known for its role in hypoxia-induced apoptosis. However, paradoxically, FAM162A is overexpressed in cancer, where its pro-apoptotic function seems overridden, suggesting an alternative role associated with mitochondrial function and cell survival. Additionally, its precise localization and topology remain controversial. ObjectivesTo assess the role of FAM162A in mitochondrial structure, dynamics, and bioenergetics and its impact on cell viability, while establishing its precise localization, orientation, and topology. Additionally, to generate a transgenic Drosophila model overexpressing human FAM162A to evaluate its effects on organismal survival under normal and stress conditions. MethodsLocalization, orientation, and topology were determined by protease protection assays in COS7 cells. Loss-and gain-of-function experiments were performed to assess mitochondrial function and turnover by confocal microscopy, immunoblots and Seahorse technology. A transgenic Drosophila model overexpressing human FAM162A was generated to evaluate organismal survival under normal and stress conditions. ResultsFAM162A is essential for maintaining mitochondrial ultrastructure and bioenergetics, thereby influencing cell viability and stress resistance. Localization studies revealed that FAM162A resides predominantly in the inner mitochondrial membrane, particularly within the cristae, where it modulates the fusion protein OPA1. Transgenic Drosophila overexpressing human FAM162A exhibited increased lifespan and locomotor activity under both normal and heat stress conditions. ConclusionFAM162A emerges as a crucial player in maintaining mitochondrial integrity and bioenergetics. Its functional role, potentially mediated through interaction with OPA1, impacts mitochondrial health, stress resistance, cellular viability, and organismal longevity.