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Coordinated transcriptional upregulation of oxidative metabolism proteins in long-lived endocrine mutant mice

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Abstract

Caloric restriction (CR), which extends lifespan in rodents, leads to increased hepatic fatty acid β-oxidation and oxidative phosphorylation (OXPHOS), with parallel changes in proteins and their mRNAs. Genetic mutants that extend lifespan, including growth hormone receptor knockout (GHRKO) and Snell dwarf (SD) mice, have lower respiratory quotient, suggesting increased reliance on fatty acid oxidation, but the molecular mechanism(s) of this metabolic shift have not yet been worked out. Here we show that both GHRKO and SD mice have significantly higher mRNA and protein levels of enzymes involved in mitochondrial and peroxisomal fatty acid β-oxidation. In addition, multiple subunits of OXPHOS complexes I-IV are upregulated in GHRKO and SD livers, and Complex V subunit ATP5a is upregulated in liver of GHRKO mice. Expression of these genes is regulated by a group of nuclear receptors and transcription factors including peroxisome proliferator-activated receptors (PPARs) and estrogen-related receptors (ERRs). We found that levels of these nuclear receptors and their co-activator PGC-1α were unchanged or downregulated in liver of GHRKO and SD mice. In contrast, NCOR1, a co-repressor for the same receptors, was significantly downregulated in the two long-lived mouse models, suggesting a plausible mechanism for the changes in FAO and OXPHOS proteins. Hepatic levels of HDAC3, a co-factor for NCOR1 transcriptional repression, were also downregulated. The role of NCOR1 is well established in the contexts of cancer and metabolic disease, but may provide new mechanistic insights into metabolic control in long-lived mouse models.

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Acknowledgements

This work was funded by National Institutes of Health (NIH) grants AG024824, AG023122, AG064706 and National Institute on Aging (NIA) grant T32-AG000114

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  1. Department of Pathology, University of Michigan School of Medicine, Ann Arbor, MI, USA

    Ahmed M. Elmansi & Richard A. Miller

  2. University of Michigan Geriatrics Center, Ann Arbor, MI, USA

    Richard A. Miller

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11357_2023_849_MOESM1_ESM.pdf

Supplementary file1 (PDF 3416 KB) Supplementary Figure 1: Fatty acid β-oxidation pathways in mitochondria and peroxisome. Created with BioRender.com. Supplementary Figure 2: Effect of Snell dwarf mutation (Pit1dw) on hepatic levels of mitochondrial fatty acid β-oxidation enzymes. (A) Representative images of western blot data for different mitochondrial FAO enzymes in liver lysates from female and male wild type (WT) and SD mice. (B-G) Scatter plots of CPT2 (B), ACADM (C), ACADL (D), ECHS1 (E), HADH (F), and ACAA2 (G). Data show mean ± S.E.M. Each symbol represents an individual mouse. n = 5-6 for each group. Two-way ANOVA was used for analysis of genotype effect, sex effect, and their interaction. Unpaired t-test was used when interaction was significant. ** P < 0.01, *** p < 0.001. Supplementary Figure 3: Hepatic levels of peroxisomal fatty acid β-oxidation enzymes in WT and SD livers. (A) Representative images of western blot data for different peroxisomal FAO enzymes in liver lysates from female and male WT and SD mice. (B-F) Scatter plots of ABCD2 (B), ACOX1 (C), ECH1 (D), EHHADH (E), and ACAA1 (F). Data show mean ± S.E.M. Each symbol represents an individual mouse. n = 5-6 for each group. Two-way ANOVA was used for analysis of genotype effect, sex effect, and their interaction. Supplementary Figure 4: Hepatic levels of OXPHOS subunit proteins in WT and SD livers. (A) Representative images of western blot data for different OXPHOS complexes subunits in liver lysates from female and male WT and SD mice. (B-J) Scatter plots of NDUFAB1 (B), NDUFAF7 (C), NDUFB11 (D), NDUFS1 (E), SDHA (F), UQCRB (G), UQCRC1 (H), COX IV (I), and ATP5a (J). Data show mean ± S.E.M. Each symbol represents an individual mouse. n = 5-6 for each group. Two-way ANOVA was used for analysis of genotype effect, sex effect, and their interaction. Supplementary Figure 5: Hepatic mRNA levels of FAO and OXPHOS genes in WT and SD livers. (A-K) Scatter plots of ACADM (A), ECHS1 (B), ACAA2 (C), ABCD2 (D), ECH1 (E), EHHADH (F), NDUFB11 (G), NDUFS1 (H), SDHA (I), UQCRB (J), and 18S (K). Data show mean ± S.E.M. Each symbol represents an individual mouse. n = 5-6 for each group. Two-way ANOVA was used for analysis of genotype effect, sex effect, and their interaction. Unpaired t-test was used when interaction was significant. *** p < 0.001, **** p < 0.0001. Supplementary Figure 6: Hepatic levels of PPAR signaling network proteins in WT and SD livers. (A) Representative images of western blot data for different nuclear receptors and their co-regulators in liver lysates from female and male WT and SD mice. (B-F) Scatter plots of PPARα (B), ERRα (C), PGC-1α (D), NCOR1 (E), and HDAC3 (F). Data show mean ± S.E.M. Each symbol represents an individual mouse. n = 5-6 for each group. Two-way ANOVA was used for analysis of genotype effect, sex effect, and their interaction

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Elmansi, A.M., Miller, R.A. Coordinated transcriptional upregulation of oxidative metabolism proteins in long-lived endocrine mutant mice. GeroScience 45, 2967–2981 (2023). https://doi.org/10.1007/s11357-023-00849-8

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