Dataset Information

Pyruvate dehydrogenase kinase 4 regulate mitochondrial dynamics

ABSTRACT: Mitochondrial dynamics provides cells with the flexibility required to adapt and respond to mitochondrial toxins, yet the mechanisms underpinning the regulation of mitochondrial dynamics machinery by these stimuli is poorly understood. Here we show that pyruvate dehydrogenase kinase 4 (PDK4) is required for cells to undergo rapid mitochondrial fragmentation when challenged with toxins. Moreover, PDK4 overexpression was sufficient to promote mitochondrial fission even in the absence of stress. Phosphoproteomic screen for PDK4 substrates identified cytoplasmic GTPase, Septin 2 (SEPT2), as the key effector molecule that acts as a receptor for DRP1 to promote mitochondrial fission. PDK4-mediated mitochondrial reshaping limits mitochondrial bioenergetics, supports cancer cell growth and revealed PDK4-SEPT2-DRP1 axis as a regulator of mitochondrial dynamics at the interface between cellular bioenergetics and mitochondrial dynamics

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Cell Culture

SUBMITTER: Byung-gyu kim

LAB HEAD: In-Kyu Lee

PROVIDER: PXD028379 | Pride | 2023-03-10

REPOSITORIES: pride

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Dataset's files

Source:

			Action	DRS
	C2C12_cont_heavy_pdk4_light_SILAC_mito.sf3	Other
	Mudpit_PDK4_mito1_1.mzid.gz	Mzid
	Mudpit_PDK4_mito1_1.mzid_Mudpit_PDK4_mito1_1.MGF	Mzid
	PDK4_mito1_1.raw	Raw
	PDK4_mito1_2.raw	Raw

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Publications

Noncanonical PDK4 action alters mitochondrial dynamics to affect the cellular respiratory status.

Thoudam Themis T Chanda Dipanjan D Sinam Ibotombi Singh IS Kim Byung-Gyu BG Kim Mi-Jin MJ Oh Chang Joo CJ Lee Jung Yi JY Kim Min-Ji MJ Park Soo Yeun SY Lee Shin Yup SY Jung Min-Kyo MK Mun Ji Young JY Harris Robert A RA Ishihara Naotada N Jeon Jae-Han JH Lee In-Kyu IK

Proceedings of the National Academy of Sciences of the United States of America 20220815 34

Dynamic regulation of mitochondrial morphology provides cells with the flexibility required to adapt and respond to electron transport chain (ETC) toxins and mitochondrial DNA-linked disease mutations, yet the mechanisms underpinning the regulation of mitochondrial dynamics machinery by these stimuli is poorly understood. Here, we show that pyruvate dehydrogenase kinase 4 (PDK4) is genetically required for cells to undergo rapid mitochondrial fragmentation when challenged with ETC toxins. Moreov ...[more]

PMID: 35969774

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Project description:Purpose:to verify Drp1-mediated biological pathways under physiological and ischemia conditions.Methods:C57BL/6 mice and Drp1 knockdown mice were used for ischemia treatment. Right femoral arteries were catheterized with polyethylene catheters for bleeding 50% of total blood volume (≈7% of weight). The ischemia time started to calculate after the model was established. A laparotomy was then carried out to obtain superior mesenteric artery tissues (SMAs) for transcriptome analysis. Series-Cluster analysis was performed to identify the global trends of mitochondrial DEGs after Drp1 knockdown. Gene ontology (GO) analysis was performed to facilitate elucidating the biological process (BP), molecular function (MF) and cellular component (CC) of unique genes in the significant or representative profiles. Results:In addition to its traditional roles in GTPase regulation and mitochondrial fission, Drp1 may also regulate actin cytoskeleton and the movement of microtubules. Besides, Drp1 may participate in the regulation of morphology and functions of other organelles, including endoplasmic reticulum, peroxisome, phagolysosome, etc. As for general organ functions, Drp1 may regulate vascular constriction and dilation. These consequences indicated the important role of Drp1 in ischemia-induced cellular regulation. Conclusions: Drp1 deficiency proves the important role of Drp1 in ischemia-induced biomedical processes through multiple potential fission-independent manners. Methods:C57BL/6 mice and Drp1 knockdown mice were used for ischemia treatment. Right femoral arteries were catheterized with polyethylene catheters for bleeding 50% of total blood volume (≈7% of weight). The ischemia time started to calculate after the model was established. A laparotomy was then carried out to obtain superior mesenteric artery tissues (SMAs) for transcriptome analysis. Series-Cluster analysis was performed to identify the global trends of mitochondrial DEGs after Drp1 knockdown. Gene ontology (GO) analysis was performed to facilitate elucidating the biological process (BP), molecular function (MF) and cellular component (CC) of unique genes in the significant or representative profiles. Results:In addition to its traditional roles in GTPase regulation and mitochondrial fission, Drp1 may also regulate actin cytoskeleton and the movement of microtubules. Besides, Drp1 may participate in the regulation of morphology and functions of other organelles, including endoplasmic reticulum, peroxisome, phagolysosome, etc. As for general organ functions, Drp1 may regulate vascular constriction and dilation. These consequences indicated the important role of Drp1 in ischemia-induced cellular regulation. Conclusions: Drp1 deficiency proves the important role of Drp1 in ischemia-induced biomedical processes through multiple potential fission-independent manners.