Dataset Information

Dysregulated cellular redox status during hyperammonemia causes mitochondrial dysfunction by inhibiting sirtuin mediated deacetylation

ABSTRACT: Perturbed metabolism of ammonia, an endogenous cytotoxic molecule, causes mitochondrial dysfunction with decreased nicotinamide adenine dinucleotide (NAD+) in skeletal muscle. Consistent with our previous report of enrichment of NAD metabolism and sirtuin pathways during hyperammonemia, NAD+-dependent Sirtuin3 (Sirt3) expression and deacetylase activity weredecreased with increased muscle protein acetylation in murine and human skeletal muscle/myotubes. Acetylomics and cell fractions showed hyperammonemia-induced hyperacetylation of critical mitochondrial and signaling molecules. Overexpression of mitochondrial targeted Lactobacillus brevis NADH oxidase (MitoLbNOX) reversed ammonia-induced oxidative dysfunction, electron transport chain (ETC) supercomplex disassembly, lower ATP content, NAD+, and redox ratio (NAD+/NADH). Protein hyperacetylation, post-mitotic senescence and lower mitochondrial sirtuin (Sirt3) expressionduring hyperammonemia were also reversed by MitoLbNOX. Sirt3 overexpression alone did not reverse ammonia-induced redox or mitochondrial dysfunction but reversed hyperacetylation and senescence. These data show that targeting redox ratio, rather than Sirt3, more consistently restores mitochondrial homeostasis and protein acetylation during hyperammonemia.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Myotube

DISEASE(S): Liver Cirrhosis

SUBMITTER: Ling Li

LAB HEAD: Srinivasan Dasarathy

PROVIDER: PXD033430 | Pride | 2023-10-24

REPOSITORIES: Pride

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Dysregulated cellular redox status during hyperammonemia causes mitochondrial dysfunction and senescence by inhibiting sirtuin-mediated deacetylation.

Mishra Saurabh S Welch Nicole N Karthikeyan Manikandan M Bellar Annette A Musich Ryan R Singh Shashi Shekhar SS Zhang Dongmei D Sekar Jinendiran J Attaway Amy H AH Chelluboyina Aruna Kumar AK Lorkowski Shuhui Wang SW Roychowdhury Sanjoy S Li Ling L Willard Belinda B Smith Jonathan D JD Hoppel Charles L CL Vachharajani Vidula V Kumar Avinash A Dasarathy Srinivasan S

Aging cell 20230426 7

Perturbed metabolism of ammonia, an endogenous cytotoxin, causes mitochondrial dysfunction, reduced NAD+ /NADH (redox) ratio, and postmitotic senescence. Sirtuins are NAD+ -dependent deacetylases that delay senescence. In multiomics analyses, NAD metabolism and sirtuin pathways are enriched during hyperammonemia. Consistently, NAD+ -dependent Sirtuin3 (Sirt3) expression and deacetylase activity were decreased, and protein acetylation was increased in human and mu ...[more]

PMID: 37101412

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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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