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MacroD1 sustains mitochondrial integrity and oxidative metabolism

ABSTRACT: The mono-ADP-ribosylhydrolase MacroD1 has recently been described to exclusively localize to mitochondria. However, to what extent and how MacroD1 controls metabolic homeostasis remains poorly understood. Here, we identify MacroD1 as a mitochondrial regulator of carbohydrate metabolism. Loss of MacroD1 in mice reduced mitochondrial load and compromised muscle function leading to decreased maximal exercise capacity. Mechanistically, knockdown of MacroD1 in C2C12 cells resulted in increased mitochondrial ROS production that ultimately led to increased mitochondrial fission. In line with these findings, proteomic and stable isotope assisted metabolomic profiling revealed that loss of MacroD1 increased glucose uptake and rewired the metabolite flux from glucose to the pentose-phosphate cycle rather than the tricarboxylic acid cycle, which increased the cells dependency on glycolysis. Glucose- and insulin-tolerance tests further showed enhanced peripheral glucose clearance following loss-of MacroD1. Together, our findings identify MacroD1 as novel regulator of metabolic homeostasis by coordinating the cellular carbohydrate fluxes and maintaining mitochondrial function.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human) Mus Musculus (mouse)

TISSUE(S): Skeletal Muscle, Myoblast, C2c12 Cell

SUBMITTER: Deena Leslie Pedrioli

LAB HEAD: Michael O. Hottiger

PROVIDER: PXD020281 | Pride | 2025-05-16

REPOSITORIES: Pride

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			Action	DRS
	20190314_03_DLP145_WTmuscleADPr_s1.raw	Raw
	20190314_04_DLP145_MD1komuscleADPr_s1.raw	Raw
	20190314_07_DLP145_WTmuscleADPr_s3.raw	Raw
	20190314_08_DLP145_MD1komuscleADPr_s2.raw	Raw
	20190314_11_DLP145_WTmuscleADPr_s4.raw	Raw

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