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IsoTopics™ – July 2016

Biochemical Pathways Affected by Mitochondrial Stress | Cambridge Isotope Laboratories, Inc.

In a landmark study, Mootha VK et al. integrated metabolomic, proteomic, and RNA profiling strategies to identify hypotheses of the biochemical pathways affected by mitochondrial stress. The results indicated a link between mitochondrial dysfunction and serine/homocysteine metabolism.  Further examination of Ser biosynthesis and transsulfuration revealed mechanisms by which mitochondrial dysfunction might compromise one-carbon synthesis in mammalian cells.  


Mitochondrial dysfunction is associated with a spectrum of human disorders, ranging from rare, inborn errors of metabolism to common, age-associated diseases such as neurodegeneration. How these lesions give rise to diverse pathology is not well understood, partly because their proximal consequences have not been well-studied in mammalian cells. Here we provide two lines of evidence that mitochondrial respiratory chain dysfunction leads to alterations in one-carbon metabolism pathways. First, using hypothesis-generating metabolic, proteomic, and transcriptional profiling, followed by confirmatory experiments, we report that mitochondrial DNA depletion leads to an ATF4-mediated increase in serine biosynthesis and transsulfuration. Second, we show that lesioning the respiratory chain impairs mitochondrial production of formate from serine, and that in some cells, respiratory chain inhibition leads to growth defects upon serine withdrawal that are rescuable with purine or formate supplementation. Our work underscores the connection between the respiratory chain and one-carbon metabolism with implications for understanding mitochondrial pathogenesis. 

Bao XR, Ong SE, Goldberger O, Peng J, Sharma R, Thompson DA, Vafai SB, Cox AG, Marutani E, Ichinose F, Goessling W, Regev A, Carr SA, Clish CB, Mootha VK.

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