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A chaperone-assisted mechanism of outer mitochondrial membrane TOM70 insertion protective against diet-induced obesity

ABSTRACT: Outer mitochondrial membrane (OMM) proteins communicate with the cytosol and other organelles including the endoplasmic reticulum (ER). This communication is important in thermogenic adipocytes to increase energy expenditure that controls body temperature and weight. However, the regulatory mechanisms of OMM protein insertion are poorly understood. Herein, stress-induced cytosolic chaperone PPID (peptidyl-prolyl isomerase D/cyclophilin 40/Cyp40) drives OMM insertion of the mitochondrial import receptor TOM70 regulating body temperature and weight in obese mice, and respiratory/thermogenic function in brown adipocytes. PPID PPIase activity and C-terminal tetratricopeptide repeats (TPR), which show specificity towards TOM70 core and C-tail domains, facilitate OMM insertion. Our results provide an unprecedented role for ER-stress-activated chaperones in controlling energy metabolism through a selective OMM protein insertion mechanism with implications in adaptation to cold temperatures and high-calorie diets.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Anna Schmoker

LAB HEAD: Pere Puigserver

PROVIDER: PXD053607 | Pride | 2024-10-03

REPOSITORIES: Pride

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			Action	DRS
	PPID_TOM.fasta	Fasta
	PPID_TOM_con_2023.07.06.filtered_cross-linked_spectra.csv	Csv
	PPID_TOM_con_2023.07.06.filtered_regular_spectra.csv	Csv
	cpd_5853A.mgf	Mgf
	cpd_5853A.raw	Raw

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A chaperone-assisted mechanism of outer mitochondrial membrane TOM70 insertion protective against diet-induced obesity

Project description:Outer mitochondrial membrane (OMM) proteins communicate with the cytosol and other organelles including the endoplasmic reticulum (ER). This communication is important in thermogenic adipocytes to increase energy expenditure that controls body temperature and weight. However, the regulatory mechanisms of OMM protein insertion are poorly understood. Herein, stress-induced cytosolic chaperone PPID (peptidyl-prolyl isomerase D/cyclophilin 40/Cyp40) drives OMM insertion of the mitochondrial import receptor TOM70 regulating body temperature and weight in obese mice, and respiratory/thermogenic function in brown adipocytes. PPID PPIase activity and C-terminal tetratricopeptide repeats (TPR), which show specificity towards TOM70 core and C-tail domains, facilitate OMM insertion. Our results provide an unprecedented role for ER-stress-activated chaperones in controlling energy metabolism through a selective OMM protein insertion mechanism with implications in adaptation to cold temperatures and high-calorie diets.

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