Drp1 controls complex II assembly and skeletal muscle metabolism by Sdhaf2 action on mitochondria-Reference-Cited by-同舟云学术

Drp1 controls complex II assembly and skeletal muscle metabolism by Sdhaf2 action on mitochondria

Published:2024-04-05 Issue:14 Volume:10 Page:
ISSN:2375-2548
Container-title:Science Advances
language:en
Short-container-title:Sci. Adv.

Author:

Zhou Zhenqi¹²^ORCID,Ma Alice¹^ORCID,Moore Timothy M.¹^ORCID,Wolf Dane M.¹³⁴,Yang Nicole¹^ORCID,Tran Peter¹^ORCID,Segawa Mayuko¹⁴^ORCID,Strumwasser Alexander R.¹,Ren Wenjuan¹,Fu Kai⁵^ORCID,Wanagat Jonathan⁶⁷^ORCID,van der Bliek Alexander M.⁸^ORCID,Crosbie-Watson Rachelle⁹¹⁰,Liesa Marc¹^ORCID,Stiles Linsey¹¹¹,Acin-Perez Rebecca¹^ORCID,Mahata Sushil¹²¹³^ORCID,Shirihai Orian¹^ORCID,Goodarzi Mark O.¹⁴^ORCID,Handzlik Michal¹⁵,Metallo Christian M.¹⁵¹⁶^ORCID,Walker David W.²⁹,Hevener Andrea L.¹²¹⁷¹⁸^ORCID

Affiliation:

1. Division of Endocrinology, Diabetes and Hypertension, Department of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.

2. Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA.

3. Department of Clinical Neurosciences, School of Clinical Medicine, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK.

4. MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK.

5. Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, CA 90095, USA.

6. Division of Geriatrics, Department of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.

7. Veterans Administration Greater Los Angeles Healthcare System, Los Angeles, CA 90073, USA.

8. Department of Biological Chemistry, University of California, Los Angeles, Los Angeles, CA 90095, USA.

9. Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA.

10. Center for Duchenne Muscular Dystrophy, University of California, Los Angeles, Los Angeles, CA 90095, USA.

11. Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA 90095, USA.

12. VA San Diego Healthcare System, San Diego, CA 92161, USA.

13. Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.

14. Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90095, USA.

15. Institute of Engineering in Medicine, University of California, San Diego, La Jolla, CA 92093, USA.

16. Molecular and Cellular Biology Laboratory, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.

17. Iris Cantor UCLA Women’s Health Research Center, University of California, Los Angeles, Los Angeles, CA 90095, USA.

18. Department of Medicine and VA Greater Los Angeles Healthcare System GRECC, Los Angeles, CA 90073, USA.

Abstract

The dynamin-related guanosine triphosphatase, Drp1 (encoded by Dnm1l ), plays a central role in mitochondrial fission and is requisite for numerous cellular processes; however, its role in muscle metabolism remains unclear. Here, we show that, among human tissues, the highest number of gene correlations with DNM1L is in skeletal muscle. Knockdown of Drp1 (Drp1-KD) promoted mitochondrial hyperfusion in the muscle of male mice. Reduced fatty acid oxidation and impaired insulin action along with increased muscle succinate was observed in Drp1-KD muscle. Muscle Drp1-KD reduced complex II assembly and activity as a consequence of diminished mitochondrial translocation of succinate dehydrogenase assembly factor 2 (Sdhaf2). Restoration of Sdhaf2 normalized complex II activity, lipid oxidation, and insulin action in Drp1-KD myocytes. Drp1 is critical in maintaining mitochondrial complex II assembly, lipid oxidation, and insulin sensitivity, suggesting a mechanistic link between mitochondrial morphology and skeletal muscle metabolism, which is clinically relevant in combatting metabolic-related diseases.

Publisher

American Association for the Advancement of Science (AAAS)

Link

https://www.science.org/doi/pdf/10.1126/sciadv.adl0389

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