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Crosstalk between Drp1 phosphorylation sites during mitochondrial remodeling and their impact on metabolic adaptation.

ABSTRACT: Mitochondria constantly undergo fusion and fission events, referred as mitochondrial dynamics, which determine mitochondrial architecture and bioenergetics. Cultured cell studies demonstrate that mitochondrial dynamics are acutely regulated by phosphorylation of the mitochondrial fission orchestrator dynamin-related protein 1 (Drp1) at S579 or S600. However, the physiological impact and crosstalk of these phosphorylation sites is poorly understood. Here, we describe the functional interrelation between S579 and S600 phosphorylation sites in vivo and their role on mitochondrial remodeling. Mice carrying a homozygous Drp1 S600A knockin (Drp1 KI) mutation display larger mitochondria and enhanced lipid oxidation and respiratory capacities, granting improved glucose tolerance and thermogenic response upon high-fat feeding. Housing mice at thermoneutrality blunts these differences, suggesting a role for the brown adipose tissue in the protection of Drp1 KI mice against metabolic damage. Overall, we demonstrate crosstalk between Drp1 phosphorylation sites and provide evidence that their modulation could be used in the treatment and prevention of metabolic diseases.

SUBMITTER: Valera-Alberni M

PROVIDER: S-EPMC8411118 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Crosstalk between Drp1 phosphorylations during mitochondrial remodelling and their impact on metabolic adaptation - Parallel reaction monitoring (PRM) mass spectrometry-based proteomic data

Project description:Mitochondria constantly undergo fusion and fission events, referred as mitochondrial dynamics, which determine intracellular mitochondrial architecture and bioenergetics. Cultured cell studies demonstrate that mitochondrial dynamics are acutely regulated by phosphorylation of the mitochondrial fission orchestrator Drp1, at S579 or S600. This dataset is linked to a study reporting on how in differentiated mouse tissues Drp1 phosphorylation at S600 acted as an upstream event for S579 phosphorylation, leading to mitochondrial fragmentation. We performed liquid chromatography mass spectrometry (LC-MS) analyses in phospho-Drp1 immunoprecipitates from BAT of vehicle or CL316,243-treated mice, following digestion with endoproteinase Glu-C to assess whether S600 and S579 phosphorylations were both occurring in the same Drp1 proteoforms or individually in different pools of Drp1 proteins. Our results certify that upon PKA stimulation, S600 and S579 phosphorylations occurred simultaneously on the same Drp1 molecular form.

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