Resumen de Functional analysis of EXD2 in mitochondrial homeostasis
One of the most fundamental events in the history of life is the origin of mitochondria. It was firstly proposed by Ivan Wallin, and later popularized by Lynn Margulis, as part of the endosymbiotic theory, that mitochondria initially arose from free-living bacteria that invaded eukaryotic cells (Wallin, 1922; Sagan, 1967). As a consequence, a mutually beneficial relationship was formed, where the eukaryote delivered protection and nutrients to the prokaryote and, in return, the prokaryote provided additional energy to its host by encoding the gene products essential for the energy-generating process known as oxidative phosphorylation (OXPHOS).
However, as this relationship became permanent over time, OXPHOS became indispensable to its host and the mitochondrion lost its autonomy, causing many of the mitochondrial genes to be transferred to the nuclear genome. The mammalian mitochondria has retained only a small subset of 37 genes in the form of a circular DNA molecule with a size of approximately 16.6 kb, including 13 essential subunits of the electron transport chain (ETC) (Anderson et al, 1981). Thus, these mitochondrial DNA (mtDNA)-encoded genes rely on nuclear encoded proteins for their transcription, processing and translation. Defects in the production or stabilization of these mtDNA-encoded subunits can lead to OXPHOS dysfunction, contributing to diverse types of human diseases, including different types of cancer, cardiomyopathies and neurodegenerative conditions (Chandra and Singh, 2011; Breuer et al, 2013).
Therefore, it has become of vital importance to understand and explore the regulatory mechanisms involved in controlling mitochondrial function. The identification and study of novel proteins that might enable particular mitochondrial functions will allow for the identification of new candidate genes for the molecular diagnosis of mitochondrial disorders.
Exonuclease 3’-5’ domain containing 2 (EXD2) is a nuclear encoded gene that has been described to promote homologous recombination by facilitating DNA end resection (Broderick et al, 2016). Here we report that EXD2 is targeted to the mitochondria and it’s critical for normal metabolism.
We found that EXD2 interacts with Complex I of the ETC and the mitoribosome and its depletion impairs mitochondrial translation, leading to a defective OXPHOS, accumulation of ROS and reduced ATP production. In Drosophila melanogaster, we observed that EXD2 deficiency leads to premature stem cell attrition in the female germline and an extension in lifespan that can be rescued by an antioxidant diet.
Together, our results define EXD2 as a mitochondrial regulator of translation and OXPHOS activity, that is required for germline stem cell maintenance and suggest that it could be a candidate gene for human metabolic disorders.
