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September 10, 2025Open Access

Mitochondrial dysfunction and defective quality control mechanisms in the kidney are not reversed by high-fat diet withdrawal in early obese mice

Key Points

Mitochondrial dysfunction was evident in kidneys after high-fat diet, with impaired bioenergetics not fully reversed by dietary withdrawal.
Reduced expression of PGC-1α and alterations in several mitochondrial dynamics proteins were noted after high-fat diet exposure in the kidneys.
Proteomic analysis identified significant changes in glutathione metabolism and fatty acid oxidation related proteins due to high-fat diet.
The findings highlight the role of mitochondrial integrity and potential therapeutic strategies for managing kidney disease progression.

Abstract

High fat diet (HFD) induces glomerulopathy and proximal tubule injury. The precise pathophysiological mechanisms triggering obesity-related kidney impairment remain elusive, especially after dietary correction. Male C57BL6/J mice (n=15) were divided in: control group (CTR) fed with standard chow; a group fed with HFD for 200 days (28-29 weeks); and a group fed with HFD for 60 days (8-9 weeks) and then with standard chow (HFDt)(∼21 weeks). Biometric data and whole-body metabolism were assessed. Expression of genes associated with mitochondrial dynamics, mitochondrial complexes and antioxidant defenses were analyzed. Kidney homogenates enriched in mitochondria were prepared and characterized by mass spectrometry-based proteomics. Kidney tissue of mice fed HFD exhibited reduced PGC-1α expression, an imbalance between fusion (increased MFN1 and decreased OPA1) and fission (decreased FIS1 and DRP1) processes. The activity of mitochondrial CI was increased, while activity of CII was decreased in the kidney after HFD and HFDt. Antioxidant defense Manganese Superoxide dismutase (MnSOD) was decreased in the kidney of HFD, while Glutathione reductase (GR) increased, with both activities being restored upon dietary reversion. Proteomic analysis showed alterations in proteins associated with glutathione and glycine metabolism, fatty acid oxidation (FAO), and peroxisomal function. HFD negatively impacted kidney glutathione related proteins (Gsta3 and Gsr) however dietary correction reverted this condition. Acsm3 protein was downregulated in kidney after HFD and upregulated after dietary correction. Some machinery is shared by mitochondria and peroxisomes, with their network being crucial particularly under stress conditions. A HFD impaired kidney FAO in peroxisomes, as evidenced by downregulation of Pecr after HFD and HFDt. Dietary correction after early-obesity mitigates the systemic metabolic dysfunction and can attenuate mitochondria dysfunction but is unable to completely restore mitochondria dynamics and bioenergetics. The results highlight the integrity of mitochondrial network as a main point for targeted therapeutic strategies aimed at preventing the progression of kidney disease.

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Braga et al. (Fri,) studied this question.

synapsesocial.com/papers/68c1b80c54b1d3bfb60ebc56 https://doi.org/https://doi.org/10.1016/j.mce.2025.112635

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