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Coenzyme Q₁₀ alleviates tacrolimus-induced mitochondrial dysfunction in kidney.

ABSTRACT: The major side effect of tacrolimus (Tac) is nephrotoxicity. We studied whether supplementation of coenzyme Q₁₀, (CoQ₁₀) a potent antioxidant, can reduce Tac-induced nephrotoxicity via improving mitochondrial function. In an in vitro study, CoQ₁₀ reduced the production of Tac-induced mitochondrial reactive oxygen species and abolished the loss of mitochondrial membrane potential in proximal tubular cell line. Assessment of mitochondrial function revealed that CoQ₁₀ decreased oxygen consumption and mitochondrial respiration rate increased by Tac, suggesting improvement of mitochondrial function to synthesize ATP with CoQ₁₀ treatment. The effect of the CoQ₁₀ in vitro study was observed in an experimental model of chronic Tac-induced nephropathy. CoQ₁₀ attenuated Tac-induced oxidative stress and was accompanied by function and histologic improvement. On electron microscopy, addition of CoQ₁₀ increased not only the number but also the volume of mitochondria compared with Tac treatment only. Our data indicate that CoQ₁₀ improves Tac-induced mitochondrial dysfunction in kidney. Supplementary CoQ₁₀ treatment may be a promising approach to reduce Tac-induced nephrotoxicity.-Yu, J. H., Lim, S. W., Luo, K., Cui, S., Quan, Y., Shin, Y. J., Lee, K. E., Kim, H. L., Ko, E. J., Chung, B. H., Kim, J. H., Chung, S. J., Yang, C. W. Coenzyme Q₁₀ alleviates tacrolimus-induced mitochondrial dysfunction in kidney.

SUBMITTER: Yu JH

PROVIDER: S-EPMC6902707 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Coenzyme Q10 alleviates tacrolimus-induced mitochondrial dysfunction in kidney.

Yu Ji Hyun JH Lim Sun Woo SW Luo Kang K Cui Sheng S Quan Yi Y Shin Yoo Jin YJ Lee Kyung Eun KE Kim Hong Lim HL Ko Eun Jeong EJ Chung Byung Ha BH Kim Ju Hwan JH Chung Sang J SJ Yang Chul Woo CW

FASEB journal : official publication of the Federation of American Societies for Experimental Biology 20190820 11

The major side effect of tacrolimus (Tac) is nephrotoxicity. We studied whether supplementation of coenzyme Q10, (CoQ10) a potent antioxidant, can reduce Tac-induced nephrotoxicity via improving mitochondrial function. In an in vitro study, CoQ10 reduced the production of Tac-induced mitochondrial reactive oxygen species and abolished the loss of mitochondrial membrane potential in proximal tubular cell line. Assessment of mitochondrial function rev ...[more]

PMID: 31431058

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Project description:BackgroundADCK genes encode aarF domain-containing mitochondrial kinases involved in coenzyme Q (CoQ) biosynthesis and regulation. Haploinsufficiency of ADCK2 in humans leads to adult-onset physical incapacity with reduced mitochondrial CoQ levels in skeletal muscle, resulting in mitochondrial myopathy and alterations in fatty acid β-oxidation. The sole current treatment for CoQ deficiencies is oral administration of CoQ10, which causes only partial recovery with postnatal treatment, underscoring the importance of early diagnosis for successful intervention.MethodsWe used Adck2 heterozygous mice to examine the influence of this gene on muscle structure, function and regeneration throughout development, growth and ageing. This investigation involved techniques including immunohistochemistry, analysis of CoQ levels, mitochondrial respiratory content, muscle transcriptome analysis and functional tests.ResultsWe demonstrated that Adck2 heterozygous mice exhibit defects from embryonic development, particularly in skeletal muscle (1102 genes deregulated). Adck2 heterozygous embryos were 7% smaller in size and displayed signs of delayed development. Prenatal administration of CoQ10 could mitigate these embryonic defects. Heterozygous Adck2 mice also showed a decrease in myogenic cell differentiation, with more severe consequences in 'aged' mice (41.63% smaller) (P < 0.01). Consequently, heterozygous Adck2 mice displayed accelerated muscle wasting associated with ageing in muscle structure (P < 0.05), muscle function (less grip strength capacity) (P < 0.001) and muscle mitochondrial respiration (P < 0.001). Furthermore, progressive CoQ10 administration conferred protective effects on mitochondrial function (P < 0.0001) and skeletal muscle (P < 0.05).ConclusionsOur work uncovered novel aspects of CoQ deficiencies, revealing defects during embryonic development in mammals for the first time. Additionally, we identified the gradual establishment and progression of the deleterious Adck2 mouse phenotype. Importantly, CoQ10 supplementation demonstrated a protective effect when initiated during development.

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Coenzyme Q₁₀ alleviates tacrolimus-induced mitochondrial dysfunction in kidney.

Publications

Coenzyme Q<sub>10</sub> alleviates tacrolimus-induced mitochondrial dysfunction in kidney.

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