FAM162A Overexpression Improves Mitochondrial Function and Extends Life in Flies
Every cell contains hundreds of mitochondria, the descendants of ancient symbiotic bacteria that have by now evolved into components of the cell. Much of their original bacterial genome has migrated into the cell nucleus to become incorporated into nuclear DNA, leaving behind only a small remnant mitochondrial genome. The primary role of mitochondria is to supply the cell with adenosine triphosphate (ATP), a chemical energy store molecule used to power cell operations. Mitochondria interact with a range of important cellular processes beyond this, however. They continue to act much like bacteria in many other ways: they replicate, fuse together, swap component parts between one another.
The behavior of mitochondria is complex and incompletely understood, as are the contributing causes and fine details of the changes that take place in mitochondria with age. In aged cells, mitochondria exhibit reduced ATP production, greater production of oxidative molecules, altered structure, leakage of DNA fragments into the cell body where they can provoke inflammation, impaired responsiveness to quality control processes that work to remove damaged mitochondria, and so forth. Their dynamics of fusion and fission change. That all of this is important to the progression of degenerative aging is well demonstrated; numerous approaches to slowing aging in short-lived species involve improvement in mitochondrial function in aged individuals.
Still, the fact that mitochondria are so complicated has hindered efforts to produce simple therapies that can dramatically improve mitochondrial function in old humans. As things stand the best approaches remain arguably less impressive than the results of undertaking more exercise. The most plausible near future approach at this time is to transplant replacement mitochondria into old people, where the challenge is reduced to being able to harvest mitochondria from cell cultures at the enormous scale required for a medical industry based on this approach. Several companies are working on this. Meanwhile, research community efforts to better understand mitochondrial function and identify points of intervention continue. Today's open access paper is an example of the type.
FAM162A is an inner mitochondrial protein known for its role in hypoxia-induced apoptosis. However, it is often overexpressed in cancer, where its pro-apoptotic function appears to be overridden, suggesting novel unknown roles in mitochondrial function and cell survival. Furthermore, its precise localization, topology, and orientation remain controversial. In this study, we aimed to assess the role of FAM162A in mitochondrial structure, dynamics, and bioenergetics and its impact on cellular and organismal stress resistance, while also establishing its localization, topology, and orientation.
To this end, localization, topology, and orientation were determined by protease-protection assays in COS7 cells. In vitro loss- and gain-of-function experiments assessed mitochondrial structure and function by confocal microscopy, immunoblotting, and Seahorse analysis, while a transgenic Drosophila model overexpressing human FAM162A was generated to evaluate organismal survival under normal and heat stress conditions.
We found that FAM162A localized to the inner mitochondrial membrane, predominantly within the cristae, and supported cristae ultrastructure, bioenergetics, and mitochondrial turnover, thereby enhancing oxidative metabolism, cell viability, and stress resistance. FAM162A expression was positively associated with the fusion protein OPA1 and interacted with OPA1 to regulate the proportion of long- and short-OPA1 isoforms. Transgenic Drosophila overexpressing human FAM162A exhibited increased lifespan and locomotor activity under both normal and heat stress conditions. Overall, FAM162A emerges as a key regulator of mitochondrial integrity and bioenergetics through its association with OPA1, confirming a novel role in cellular health and stress resistance.