Mitochondria are responsible for the production of 90% of cellular ATP during oxidative phosphorylation (OXPHOS), a process that couples cellular respiration to ATP production. Defects in the mitochondrial respiratory chain (RC) underlie many inherited mitochondrial disorders and have been implicated in multiple neurological and metabolic diseases.
The development of treatments for mitochondrial dysfunction has been the focus of intensive research across multiple labs; however, effective treatments have proved to be elusive. Several strategies for treatment development are currently being followed. The majority of these involve increasing the production of ATP by the RC, either by providing more substrate for OXPHOS in the form of NADH precursors, increasing mitochondrial biogenesis to add to the pool of mitochondria available for ATP production, targeting dysfunctional mitochondria for degradation via mitophagy, or degrading mitochondrial genomes harboring disease-causing mutations and thus improving mitochondrial health.
Using a large-scale CRISPR Cas9-mediated whole-genome knockout screen, the authors were able to identify a set of genes whose ablation improved survival in cells with pharmacologically impaired RC complex III. Surprisingly, the most effective genetic suppressor of mitochondrial disease was inhibition of Von Hippel-Lindau (VHL) factor, a key regulator in the hypoxia response pathway and recognized tumor suppressor protein.
Under physiologically normoxic conditions, a group of hypoxia-inducible transcription factors (HIFs) are produced and are hydroxylated, signaling them for ubiquitination and subsequent degradation by the VCB-Cull2 complex. VHL, a core component of this complex, is the E3 ubiquitin ligase. Under hypoxic conditions, this hydroxylation step does not occur, thus preventing degradation of HIFs and allowing cells to respond in environments with low oxygen tension.
The authors also show that VHL knockout cells are resistant to other inhibitors of OXPHOS (RC complex I and FoF1 ATP-synthase). Further, by using a small-molecule inhibitor (FG-4592) of the HIF hydroxylating enzyme prolyl-hydroxylase, author rescued a growth defect in cell lines with Complex I, III, or V inhibition.
http://www.cell.com/molecular-cell/abstract/S1097-2765(16)30010-7
Treating Mitochondrial Disease with Hypoxia
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