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Mitochondrial MOF regulates energy metabolism in heart failure by ATP5B hyperacetylation

ABSTRACT: In current study, we found that the protein level of MOF in mitochondrial was significantly increased during the course of heart failure. Overexpression of mtMOF induced cardiac hypertrophy and energy metabolism disorder, as well as heart failure. When combined with mtMOF overexpression and SIRT3 deficiency, the acetylation level in cardiomyocytes was significantly upregulated, accompanied with serious enegergy abnormal and cardiac function injury. Mitochondrial substrates of MOF was identified by using acetylated proteomic analysis. We demonstrated that mtMOF and SIRT3 exhibited damage effect by regulating the acetylation level of the common substrate ATP5B. This study clarified the acetyltransferase activity of MOF in mitochondria, providing a new theoretical basis for the acetylation regulation mode of mitochondrial proteins. In addition, we provides a new research idea for exploring the relationship between hyperacetylation and energy metabolism disorder and heart failure.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Permanent Cell Line Cell, Cell Culture

SUBMITTER: YUYU YOU

LAB HEAD: Mao Yang

PROVIDER: PXD044074 | Pride | 2024-12-09

REPOSITORIES: Pride

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			Action	DRS
	202001102_HYH-HEK293T_mito-trypsin_TMT10_Kac_0920_2h_10HCD_20ng_1.msfView	Msf
	202001102_HYH-HEK293T_mito-trypsin_TMT10_Kac_0920_2h_10HCD_20ng_1.raw	Raw
	checksum.txt	Txt

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Project description:BACKGROUND: Strategies to increase cellular NAD+ (oxidized nicotinamide adenine dinucleotide) level have prevented cardiac dysfunction in multiple models of heart failure, but molecular mechanisms remain unclear. Little is known about the benefits of NAD+-based therapies in failing hearts after the symptoms of heart failure have appeared. Most pretreatment regimens suggested mechanisms involving activation of sirtuin, especially Sirt3 (sirtuin 3), and mitochondrial protein acetylation. METHODS: We induced cardiac dysfunction by pressure overload in SIRT3-deficient (knockout) mice and compared their response with nicotinamide riboside chloride treatment with wild-type mice. To model a therapeutic approach, we initiated the treatment in mice with established cardiac dysfunction. RESULTS: We found nicotinamide riboside chloride improved mitochondrial function and blunted heart failure progression. Similar benefits were observed in wild-type and knockout mice. Boosting NAD+ level improved the function of NAD(H) redox sensitive SDR (short-chain dehydrogenase/reductase) family proteins. Upregulation of Mrpp2 (mitochondrial ribonuclease P protein 2), a multifunctional SDR protein and a subunit of mitochondrial ribonuclease P, improves mitochondrial DNA transcripts processing and electron transport chain function. Activation of SDRs in the retinol metabolism pathway stimulates RXRα (retinoid X receptor α)/PPARα (proliferator-activated receptor α) signaling and restores mitochondrial oxidative metabolism. Downregulation of Mrpp2 and impaired mitochondrial ribonuclease P were found in human failing hearts, suggesting a shared mechanism of defective mitochondrial biogenesis in mouse and human heart failure. CONCLUSIONS: These findings identify SDR proteins as important regulators of mitochondrial function and molecular targets of NAD+-based therapy. Furthermore, the benefit is observed regardless of Sirt3-mediated mitochondrial protein deacetylation, a widely held mechanism for NAD+-based therapy for heart failure. The data also show that NAD+-based therapy can be useful in pre-existing heart failure.

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Mitochondrial MOF regulates energy metabolism in heart failure by ATP5B hyperacetylation

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