Understanding the Role of Mitochondrial Dysfunction in Mucopolysaccharidosis Type VII

Mandal, Nishan (2025) Understanding the Role of Mitochondrial Dysfunction in Mucopolysaccharidosis Type VII. PhD thesis, Indian Institute of Science Education and Research Kolkata.

Text (PhD thesis of Nishan Mandal (18RS056)) 18RS056.pdf - Submitted Version Restricted to Repository staff only Download (4MB)

Abstract

Progressive neuromuscular defects are hallmarks of Mucopolysaccharidosis VII (MPS VII), a lysosomal storage disorder caused by β-glucuronidase (β-GUS) deficiency. However, the underlying mechanisms driving neuromuscular degeneration in MPS VII remain poorly understood. To investigate MPS VII pathogenesis, our lab has generated a CG2135 knockout Drosophila model, the fly homologue of β-GUS. CG2135-/- flies recapitulated the cardinal features of MPS VII with prominent neuromuscular degeneration. Careful analysis of CG2135-/- fly brains revealed accumulation of engorged lysosomes and ubiquitinated protein. CG2135-/- flies also exhibited impaired autophagic turnover, suggesting a disruption in cellular quality control mechanisms. Recent observations also revealed accumulations of MitoTracker-positive puncta in the CG2135-/- fly brain. However, their role in disease progression remains elusive. Building on these initial observations, we systematically investigated the causes and consequences of mitochondrial accumulation in these fly brains. Our findings demonstrated impaired mitophagy-mediated mitochondrial clearance, leading to abnormal accumulations of damaged mitochondria with distorted cristae and reduced membrane potential. Elevated mitochondrial dysfunction severely compromised cellular energy homeostasis, as evidenced by a drastic reduction in brain ATP levels. Energy depletion subsequently triggered apoptotic death of neuronal and non-neuronal brain cells, with dopaminergic neurons being especially vulnerable. Notably, treatment with resveratrol restored mitophagy, prevented ATP depletion, and conferred neuroprotection, highlighting mitophagy as a potential therapeutic target. Interestingly, β-glucuronidase in Drosophila is encoded by two genes, CG2135 and CG15117. To assess the impact of complete β-GUS deficiency, we generated a double knockout (DKO) model lacking both CG2135 and CG15117. The DKO flies exhibited the most severe phenotypes, including drastically reduced survival and progressive locomotor decline. However, in the brain, ATP depletion was observed only after 45 days, which failed to explain the early loss of locomotor activity in CG2135-/- and DKO flies. This motivated us to check mitochondrial status in these fly muscles. Mitochondrial defects were more pronounced and appeared at an earlier age in muscle than in brain tissue, suggesting that muscle degeneration plays a key role in mobility loss. In conclusion, our findings identify elevated mitochondrial dysfunction caused by impaired mitophagy as a central driver of MPS VII pathogenesis. Furthermore, we demonstrate that restoring mitochondrial function through pharmacological targeting of the mitophagy pathway holds therapeutic potential for mitigating disease progression.

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