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PINK1 and Parkin Ameliorate the Loss of Motor Activity and Mitochondrial Dysfunction Induced by Peripheral Neuropathy-Associated HSPB8 Mutants in Drosophila Models.

ABSTRACT: Charcot-Marie-Tooth disease (CMT) is a group of inherited peripheral nerve disorders characterized by progressive muscle weakness and atrophy, sensory loss, foot deformities and steppage gait. Missense mutations in the gene encoding the small heat shock protein HSPB8 (HSP22) have been associated with hereditary neuropathies, including CMT. HSPB8 is a member of the small heat shock protein family sharing a highly conserved α-crystallin domain that is critical to its chaperone activity. In this study, we modeled HSPB8 mutant-induced neuropathies in Drosophila. The overexpression of human HSPB8 mutants in Drosophila neurons produced no significant defect in fly development but led to a partial reduction in fly lifespan. Although these HSPB8 mutant genes failed to induce sensory abnormalities, they reduced the motor activity of flies and the mitochondrial functions in fly neuronal tissue. The motor defects and mitochondrial dysfunction were successfully restored by PINK1 and parkin, which are Parkinson's disease-associated genes that have critical roles in maintaining mitochondrial function and integrity. Consistently, kinetin riboside, a small molecule amplifying PINK1 activity, also rescued the loss of motor activity in our HSPB8 mutant model.

SUBMITTER: Kang KH

PROVIDER: S-EPMC10045361 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature

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PINK1 and Parkin Ameliorate the Loss of Motor Activity and Mitochondrial Dysfunction Induced by Peripheral Neuropathy-Associated HSPB8 Mutants in <i>Drosophila</i> Models.

Kang Kyong-Hwa KH Han Ji Eun JE Kim Hyunjin H Kim Sohee S Hong Young Bin YB Yun Jeanho J Nam Soo Hyun SH Choi Byung-Ok BO Koh Hyongjong H

Biomedicines 20230309 3

Charcot-Marie-Tooth disease (CMT) is a group of inherited peripheral nerve disorders characterized by progressive muscle weakness and atrophy, sensory loss, foot deformities and steppage gait. Missense mutations in the gene encoding the small heat shock protein HSPB8 (HSP22) have been associated with hereditary neuropathies, including CMT. HSPB8 is a member of the small heat shock protein family sharing a highly conserved α-crystallin domain that is critical to its chaperone activity. In this st ...[more]

PMID: 36979812

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Project description:BackgroundMechanical ventilation (MV) often leads to ventilation-induced diaphragm dysfunction (VIDD). Although the development of this disorder had been linked to oxidative stress, mitochondrial energy deficiency, autophagy activation, and apoptosis in the diaphragm, it remains unclear whether the activation of mitophagy can induce VIDD. With our research, our endeavor is to uncover whether PTEN-induced putative kinase 1 (PINK1)/Parkin-mediated mitophagy affects the MV-caused diaphragmatic dysfunction.MethodsSprague-Dawley rats were subjected to MV treatment for 6 h (MV-6h), 12 h (MV-12h), or 24 h (MV-24h). Post MV, the diaphragm muscle compound action potential (CMAP) and cross-sectional areas (CSAs) of the diaphragm of these rats were measured. The levels of proteins of interest were examined to assess muscle health, mitochondrial dynamics, and mitophagy in the diaphragm. The co-localization of PINK1 with the mitochondrial protein marker tom20 was examined, as well as transmission electron microscopy analysis to detect changes in diaphragm mitochondrial ultrastructure.ResultsMV-12h and MV-24h treatments resulted in a decrease in CSA of diaphragm and CMAP amplitude. In addition, the expressions of F-box (MFAbx), muscle-specific ring finger 1 (MURF1), PINK1, and p62 were elevated in rats treated with MV for 12 h and 24 h, while mfn2 expression was reduced. Rats following MV-24h treatment displayed an increase in mitochondrial dynamic protein (Drp1) and Parkin expression and microtubule-associated protein 1 light chain 3/1 (LC3II/I) ratio. Moreover, decreased SOD and GSH activity and membrane potential were observed after MV-12h and MV-24h treatment, while H2O2 activity increased after MV-24h treatment. In addition, a strong co-localization between PINK1 and tom20 was identified.ConclusionThese results reveal that MV leads to various changes in mitochondrial dynamics and significantly increases the mitophagy levels, which subsequently cause the variation in diaphragmatic function and muscle atrophy, indicating that mitophagy could be one of the possible mechanisms by which MV induces diaphragmatic dysfunction.The reviews of this paper are available via the supplemental material section.

Dataset Information

PINK1 and Parkin Ameliorate the Loss of Motor Activity and Mitochondrial Dysfunction Induced by Peripheral Neuropathy-Associated HSPB8 Mutants in Drosophila Models.

Publications

PINK1 and Parkin Ameliorate the Loss of Motor Activity and Mitochondrial Dysfunction Induced by Peripheral Neuropathy-Associated HSPB8 Mutants in <i>Drosophila</i> Models.

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