Aberrant ER-Mitochondria Communication in Human Mitochondrial Disease

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Mitochondrial disease, defined as a group of disorders due to defects in the respiratory chain/oxidative-phosphorylation system (OxPhos), comprises an important group of pathologies that are challenging to study and treat, as they are among the most heterogeneous human conditions at every level: clinical, biochemical, and genetic. Mitochondria are under dual genetic control, dependent on both nuclear DNA (nDNA) and mitochondrial DNA (mtDNA). Pathogenic mutations in genes encoded by both genomes give rise to mitochondrial disease, many of which are neurodegenerative disorders that typically are both devastating and ultimately fatal. Mutations in mtDNA genes affect structural subunits of the OxPhos system, whereas mutations in nDNA genes are more numerous and diverse, as they encode not only a large number of OxPhos subunits but also factors needed for the proper synthesis, assembly, and functioning of the OxPhos machinery. We recently discovered that in cells from patients with mitochondrial disease there is a significant disruption in the intimate communication, both physical and biochemical, between mitochondria and endoplasmic reticulum (ER) at "mitochondria-associated ER membranes (MAM)". MAM is a central locus for maintaining cellular cholesterol, phospholipid, and calcium homeostasis, as well as regulating mitochondrial bioenergetics and dynamics (organellar fusion, fission, and positioning). Based on this finding, we hypothesize that reductions in oxidative energy metabolism can disrupt ER-mitochondrial communication, with serious consequences for cell survivability that go well beyond that of reduced ATP output. The objectives of this application - and our Specific Aims - are thus threefold: (1) to deduce the genetic and biochemical circumstances under which OxPhos deficits affect MAM (the "phenotypic landscape"), by analyzing cells from patients with known mutations in nDNA and mtDNA causing OxPhos deficiency, and by perturbing bioenergetics with specific OxPhos toxins; (2) to gain insight into the mechanism by which this occurs, using both biased (i.e. targeted) and unbiased approaches to identify OxPhos-related factors that affect ER-mitochondrial connectivity; and (3) to determine if we can use either genetic or pharmacological approaches to improve ER-mitochondrial communication in cells with genetically-compromised bioenergetics, thereby revealing "latent" OxPhos potential (i.e. improved OxPhos output and efficiency) and increasing bioenergetic output, even in cells with a high mutation load. Our discovery of an "OxPhos-MAM connection" has revealed a hitherto unknown pathogenetic role of altered inter-organellar communication in mitochondrial disease. In turn, this has opened up a new way of thinking about the pathogenesis and treatment of mitochondrial disease. A therapeutic strategy based on "fixing" ER-mitochondrial connectivity to re-normalize MAM function will likely be generalizable to a large number of mitochondrial disorders.