Mitochondria are the main producers of energy in cells, and lysosomes recycle cellular debris that accumulates during normal function of our cells. Neurons are highly dependent on energy production by mitochondria, and because of their activity, neurons produce an abundance of cellular debris that must be cleared by lysosomes. Scientists at Northwestern Medicine have now uncovered those mutations in a gene called parkin, which contribute to familial forms of Parkinson’s disease, result in a breakdown of contacts between lysosomes and mitochondria. This discovery opens a new avenue for Parkinson’s therapeutics.
The findings are published in Science Advances in an article titled, “Parkin regulates amino acid homeostasis at mitochondria-lysosome (M/L) contact sites in Parkinson’s disease.”
“Mutations in the E3 ubiquitin ligase parkin are the most common cause of early-onset Parkinson’s disease (PD),” wrote the researchers. “Although parkin modulates mitochondrial and endolysosomal homeostasis during cellular stress, whether parkin regulates mitochondrial and lysosomal cross-talk under physiologic conditions remains unresolved. Using transcriptomics, metabolomics, and super-resolution microscopy, we identify amino acid metabolism as a disrupted pathway in iPSC-derived dopaminergic neurons from patients with parkin PD.”
In a prior study, published in Nature, Dimitri Krainc, MD, PhD, chair of neurology and director of Simpson Querrey Center for Neurogenetics at Northwestern University Feinberg School of Medicine, and his group discovered that lysosomes and mitochondria form contacts with each other. After the initial discovery, Northwestern scientists tried to understand the function of these contacts in Parkinson’s disease.
In the current study, the scientists found that lysosomes provide important amino acids that support the function of mitochondria. However, they also found that in some forms of Parkinson’s disease, lysosomes cannot serve as a “helping hand” to mitochondria because the contacts between the two organelles are disrupted. This results in dysfunctional mitochondria and ultimately degeneration of vulnerable neurons in Parkinson’s disease.
“Findings from this study suggest that dysregulation of mitochondria-lysosome contacts contributes to the Parkinson’s disease pathophysiology,” said Krainc. “We propose that restoring such mitochondria-lysosome contacts represents an important new therapeutic opportunity for Parkinson’s disease.”
“Mitochondrial and lysosomal metabolomics in parkin PD neurons demonstrated accumulation of lysosomal amino acids and deficiency of mitochondrial amino acids, which was partially restored by promoting mitochondria-lysosome tethering. Thus, our data highlight a function of parkin in promoting mitochondrial and lysosomal amino acid homeostasis via regulation of mitochondria-lysosome contact sites,” concluded the researchers.
From a broader perspective, this study opens a new avenue of research in neurodegenerative disorders, by highlighting the importance of direct communication and collaboration between cellular organelles in the pathogenesis of these disorders.
