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

Zhenqi Zhou; Alice Ma; Timothy M. Moore; Dane M. Wolf; Nicole Yang; Peter Tran; Mayuko Segawa; Alexander R. Strumwasser; Wenjuan Ren; Kai Fu; Jonathan Wanagat; Alexander M. van der Bliek; Rachelle Crosbie-Watson; Marc Liesa; Linsey Stiles; Rebecca Acin-Perez; Sushil Mahata; Orian Shirihai; Mark O. Goodarzi; Michal Handzlik; Christian M. Metallo; David W. Walker; Andrea L. Hevener

doi:10.1126/sciadv.adl0389

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

Zhenqi Zhou, Alice Ma, Timothy M. Moore, Dane M. Wolf, Nicole Yang, Peter Tran, Mayuko Segawa, Alexander R. Strumwasser, Wenjuan Ren, Kai Fu, Jonathan Wanagat, Alexander M. van der Bliek, Rachelle Crosbie-Watson, Marc Liesa, Linsey Stiles, Rebecca Acin-Perez, Sushil Mahata, Orian Shirihai, Mark O. Goodarzi, Michal HandzlikChristian M. Metallo, David W. Walker, Andrea L. Hevener

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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.

Original language	English
Article number	eadl0389
Journal	Science advances
Volume	10
Issue number	14
DOIs	https://doi.org/10.1126/sciadv.adl0389
State	Published - 5 Apr 2024
Externally published	Yes

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Zhou, Z., Ma, A., Moore, T. M., Wolf, D. M., Yang, N., Tran, P., Segawa, M., Strumwasser, A. R., Ren, W., Fu, K., Wanagat, J., van der Bliek, A. M., Crosbie-Watson, R., Liesa, M., Stiles, L., Acin-Perez, R., Mahata, S., Shirihai, O., Goodarzi, M. O., ... Hevener, A. L. (2024). Drp1 controls complex II assembly and skeletal muscle metabolism by Sdhaf2 action on mitochondria. Science advances, 10(14), Article eadl0389. https://doi.org/10.1126/sciadv.adl0389

@article{226941a1d77c427ab13d7f6288f1042d,

title = "Drp1 controls complex II assembly and skeletal muscle metabolism by Sdhaf2 action on mitochondria",

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.",

author = "Zhenqi Zhou and Alice Ma and Moore, {Timothy M.} and Wolf, {Dane M.} and Nicole Yang and Peter Tran and Mayuko Segawa and Strumwasser, {Alexander R.} and Wenjuan Ren and Kai Fu and Jonathan Wanagat and {van der Bliek}, {Alexander M.} and Rachelle Crosbie-Watson and Marc Liesa and Linsey Stiles and Rebecca Acin-Perez and Sushil Mahata and Orian Shirihai and Goodarzi, {Mark O.} and Michal Handzlik and Metallo, {Christian M.} and Walker, {David W.} and Hevener, {Andrea L.}",

year = "2024",

month = apr,

day = "5",

doi = "10.1126/sciadv.adl0389",

language = "English",

volume = "10",

journal = "Science advances",

issn = "2375-2548",

publisher = "American Association for the Advancement of Science",

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Zhou, Z, Ma, A, Moore, TM, Wolf, DM, Yang, N, Tran, P, Segawa, M, Strumwasser, AR, Ren, W, Fu, K, Wanagat, J, van der Bliek, AM, Crosbie-Watson, R, Liesa, M, Stiles, L, Acin-Perez, R, Mahata, S, Shirihai, O, Goodarzi, MO, Handzlik, M, Metallo, CM, Walker, DW & Hevener, AL 2024, 'Drp1 controls complex II assembly and skeletal muscle metabolism by Sdhaf2 action on mitochondria', Science advances, vol. 10, no. 14, eadl0389. https://doi.org/10.1126/sciadv.adl0389

TY - JOUR

T1 - Drp1 controls complex II assembly and skeletal muscle metabolism by Sdhaf2 action on mitochondria

AU - Zhou, Zhenqi

AU - Ma, Alice

AU - Moore, Timothy M.

AU - Wolf, Dane M.

AU - Yang, Nicole

AU - Tran, Peter

AU - Segawa, Mayuko

AU - Strumwasser, Alexander R.

AU - Ren, Wenjuan

AU - Fu, Kai

AU - Wanagat, Jonathan

AU - van der Bliek, Alexander M.

AU - Crosbie-Watson, Rachelle

AU - Liesa, Marc

AU - Stiles, Linsey

AU - Acin-Perez, Rebecca

AU - Mahata, Sushil

AU - Shirihai, Orian

AU - Goodarzi, Mark O.

AU - Handzlik, Michal

AU - Metallo, Christian M.

AU - Walker, David W.

AU - Hevener, Andrea L.

PY - 2024/4/5

Y1 - 2024/4/5

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85190081201&partnerID=8YFLogxK

U2 - 10.1126/sciadv.adl0389

DO - 10.1126/sciadv.adl0389

M3 - Article

C2 - 38569044

AN - SCOPUS:85190081201

SN - 2375-2548

VL - 10

JO - Science advances

JF - Science advances

IS - 14

M1 - eadl0389

ER -

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

Abstract

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