Mitochondrial Dysfunction and Decreased Cytochrome c in Cell and Animal Models of Machado-Joseph Disease
Filipa Almeida1, Ildete L Ferreira1,2, Luana Naia1,2
1CNC-UC-Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal.
Abstract:
Mitochondrial dysfunction has been described in many neurodegenerative disorders; however, there is less information regarding mitochondrial deficits in Machado-Joseph disease (MJD), a polyglutamine (polyQ) disorder caused by CAG repeat expansion in the ATXN3 gene. In the present study, we characterized the changes in mitochondrial function and biogenesis markers in two MJD models, CMVMJD135 (MJD135) transgenic mice at a fully established phenotype stage and tetracycline-regulated PC6-3 Q108 cell line expressing mutant ataxin-3 (mATXN3). We detected mATXN3 in the mitochondrial fractions of PC6-3 Q108 cells, suggesting the interaction of expanded ATXN3 with the organelle. Interestingly, in both the cerebella of the MJD135 mouse model and in PC6-3 Q108 cells, we found decreased mitochondrial respiration, ATP production and mitochondrial membrane potential, strongly suggesting mitochondrial dysfunction in MJD. Also, in PC6-3 Q108 cells, an additional enhanced glycolytic flux was observed. Supporting the functional deficits observed in MJD mitochondria, MJD135 mouse cerebellum and PC6-3 Q108 cells showed reduced cytochrome c mRNA and protein levels. Overall, our findings show compromised mitochondrial function associated with decreased cytochrome c levels in both cell and animal models of MJD.
Insights
Machado-Joseph disease (MJD), a polyglutamine disorder, shows significant mitochondrial dysfunction. This study reveals impaired respiration, ATP production, and reduced cytochrome c in MJD models, highlighting key cellular deficits.
Area of Science:
- Neuroscience
- Cell Biology
- Genetics
Background:
- Mitochondrial dysfunction is implicated in neurodegenerative diseases.
- Machado-Joseph disease (MJD) is a polyglutamine disorder caused by ATXN3 gene CAG repeat expansion.
- Limited information exists on mitochondrial deficits in MJD.
Purpose of the Study:
- To characterize mitochondrial function and biogenesis markers in MJD models.
- To investigate the role of mutant ataxin-3 (mATXN3) in mitochondrial deficits.
- To explore changes in cytochrome c levels in MJD.
Main Methods:
- Utilized CMVMJD135 transgenic mice and PC6-3 Q108 cell lines expressing mATXN3.
- Detected mATXN3 in mitochondrial fractions.
- Assessed mitochondrial respiration, ATP production, membrane potential, and glycolytic flux.
- Quantified cytochrome c mRNA and protein levels.
Main Results:
- mATXN3 was found in mitochondrial fractions of PC6-3 Q108 cells.
- Decreased mitochondrial respiration, ATP production, and membrane potential were observed in both MJD models.
- Enhanced glycolytic flux was noted in PC6-3 Q108 cells.
- Reduced cytochrome c mRNA and protein levels were detected in MJD135 mouse cerebellum and PC6-3 Q108 cells.
Conclusions:
- Mitochondrial dysfunction is a significant feature of Machado-Joseph disease.
- Compromised mitochondrial function is associated with decreased cytochrome c levels in MJD.
- Findings provide insights into the cellular pathology of MJD.
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