MacroD1 sustains mitochondrial integrity and oxidative metabolism

The mono-ADP-ribosylhydrolase MacroD1 has been recently reported to localize to mitochondria exclusively. However, the extent and means by which MacroD1 regulates metabolic homeostasis remains unclear. Here we show that the absence of MacroD1 in mice decreased mitochondrial load and negatively impacted muscle function, reducing maximal exercise capacity. Knockdown of MacroD1 in C2C12 myoblast cells amplified the production of reactive oxygen species which ultimately resulted in increased mitochondrial fission. Proteomic and metabolomic profiling showed that loss of MacroD1 re-routed metabolite flux from glucose to the pentose-phosphate cycle instead of the tricarboxylic acid cycle to support the production of antioxidants, including glutathione and NADPH. This resulted in increased glucose uptake and dependency both in vitro and in vivo. Hence, our research establishes MacroD1 as a regulator of metabolic homeostasis, which ensures the coordination of cellular carbohydrate flux and optimal mitochondrial function.

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Publication Details

Journal
Nature Communications
Published
2025-08-15
DOI
https://doi.org/10.1038/s41467-025-62410-9
Citations
1
Primary Topic
Mitochondrial Function and Pathology
Type
article
Field-Weighted Citation Impact
0.81

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MacroD1 sustains mitochondrial integrity and oxidative metabolism

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MacroD1 sustains mitochondrial integrity and oxidative metabolism

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article en
1 citations

Abstract

The mono-ADP-ribosylhydrolase MacroD1 has been recently reported to localize to mitochondria exclusively. However, the extent and means by which MacroD1 regulates metabolic homeostasis remains unclear. Here we show that the absence of MacroD1 in mice decreased mitochondrial load and negatively impacted muscle function, reducing maximal exercise capacity. Knockdown of MacroD1 in C2C12 myoblast cells amplified the production of reactive oxygen species which ultimately resulted in increased mitochondrial fission. Proteomic and metabolomic profiling showed that loss of MacroD1 re-routed metabolite flux from glucose to the pentose-phosphate cycle instead of the tricarboxylic acid cycle to support the production of antioxidants, including glutathione and NADPH. This resulted in increased glucose uptake and dependency both in vitro and in vivo. Hence, our research establishes MacroD1 as a regulator of metabolic homeostasis, which ensures the coordination of cellular carbohydrate flux and optimal mitochondrial function.

Nature CommunicationsVol. 16(1)
University of Zurich (CH), Universitätsmedizin Greifswald (DE), Life Science Zurich (CH), Czech Academy of Sciences, Institute of Physiology (CZ), Technische Universität Braunschweig (DE)
National Science Foundation, Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung, Universität Zürich
Openalex Percentile: Top 25%
Mitochondrial Function and Pathology
0.81
DOIOpen Access PDFOpenAlex
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