Effects of Parkin on the Mitochondrial Genome in the Heart and Brain of Mitochondrial Mutator Mice.

Eliezer Z Lichter, Andrew J Trease, Kathryn Cooper, Kelly L Stauch, Howard S Fox

Advanced biology 2023 Aug

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Mitochondrial dysfunction has been implicated in neurodegenerative diseases like Parkinson's disease (PD). This study investigates the role of Parkin, a protein involved in mitochondrial quality control, and strongly linked to PD, in the context of mitochondrial DNA (mtDNA) mutations. Mitochondrial mutator mice (PolgD257A/D257A ) (Polg) are used and bred with Parkin knockout (PKO) mice or mice with disinhibited Parkin (W402A). In the brain, mtDNA mutations are analyzed in synaptosomes, presynaptic neuronal terminals, which are far from neuronal soma, which likely renders mitochondria there more vulnerable compared with brain homogenate. Surprisingly, PKO results in reduced mtDNA mutations in the brain but increased control region multimer (CRM) in synaptosomes. In the heart, both PKO and W402A lead to increased mutations, with W402A showing more mutations in the heart than PKO. Computational analysis reveals many of these mutations are deleterious. These findings suggest that Parkin plays a tissue-dependent role in regulating mtDNA damage response, with differential effects in the brain and heart. Understanding the specific role of Parkin in different tissues may provide insights into the underlying mechanisms of PD and potential therapeutic strategies. Further investigation into these pathways can enhance the understanding of neurodegenerative diseases associated with mitochondrial dysfunction. © 2023 The Authors. Advanced Biology published by Wiley-VCH GmbH.

Citation

Eliezer Z Lichter, Andrew J Trease, Kathryn Cooper, Kelly L Stauch, Howard S Fox. Effects of Parkin on the Mitochondrial Genome in the Heart and Brain of Mitochondrial Mutator Mice. Advanced biology. 2023 Aug;7(8):e2300154