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Metabolic reprogramming in the OPA1-deficient cells

Dai, Wenting and Wang, Zhichao and Wang, Qiong A. and Chan, David C. and Jiang, Lei (2022) Metabolic reprogramming in the OPA1-deficient cells. Cellular and Molecular Life Sciences, 79 (10). Art. No. 517. ISSN 1420-682X. doi:10.1007/s00018-022-04542-5.

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OPA1, a dynamin-related GTPase mutated in autosomal dominant optic atrophy, is essential for the fusion of the inner mitochondrial membrane. Although OPA1 deficiency leads to impaired mitochondrial morphology, the role of OPA1 in central carbon metabolism remains unclear. Here, we aim to explore the functional role and metabolic mechanism of OPA1 in cell fitness beyond the control of mitochondrial fusion. We applied [U-¹³C]glucose and [U-13C]glutamine isotope tracing techniques to OPA1-knockout (OPA1-KO) mouse embryonic fibroblasts (MEFs) compared to OPA1 wild-type (OPA1-WT) controls. Furthermore, the resulting tracing data were integrated by metabolic flux analysis to understand the underlying metabolic mechanism through which OPA1 deficiency reprograms cellular metabolism. OPA1-deficient MEFs were depleted of intracellular citrate, which was consistent with the decreased oxygen consumption rate in these cells with mitochondrial fission that is not balanced by mitochondrial fusion. Whereas oxidative glucose metabolism was impaired, OPA1-deficient cells activated glutamine-dependent reductive carboxylation and subsequently relied on this reductive metabolism to produce cytosolic citrate as a predominant acetyl-CoA source for de novo fatty acid synthesis. Prevention of cytosolic glutamine reductive carboxylation by GSK321, an inhibitor of isocitrate dehydrogenase 1 (IDH1), largely repressed lipid synthesis and blocked cell proliferation in OPA1-deficient MEFs. Our data support that, when glucose oxidation failed to support lipogenesis and proliferation in cells with unbalanced mitochondrial fission, OPA1 deficiency stimulated metabolic anaplerosis into glutamine-dependent reductive carboxylation in an IDH1-mediated manner.

Item Type:Article
Related URLs:
URLURL TypeDescription ReadCube access
Wang, Qiong A.0000-0003-2224-4287
Chan, David C.0000-0002-0191-2154
Jiang, Lei0000-0002-8596-556X
Additional Information:We thank the Light Microscopy Core at City of Hope Medical Center for technical assistance. The work was supported by Caltech-City of Hope Biomedical Research Initiative awarded to Lei Jiang, David Chan, and Qiong A. Wang, grant NIH R35 GM127147 to David Chan, and P30CA033572 to City of Hope. Qiong A. Wang was also supported by National Institutes of Health grants R01AG063854, R01HD096152, R01DK128907, and the American Diabetes Association Junior Faculty Development Award 1-19-JDF-023.
Funding AgencyGrant Number
Caltech-City of Hope Biomedical InitiativeUNSPECIFIED
NIHR35 GM127147
American Diabetes Association Research Foundation1-19-JDF-023
Issue or Number:10
Record Number:CaltechAUTHORS:20220922-931611600.11
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Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:117114
Deposited By: Melissa Ray
Deposited On:29 Sep 2022 22:05
Last Modified:29 Sep 2022 22:05

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