| dc.description.abstracteng | Defects in metabolism result in various diseases, with neurodegeneration being one of the most prevalent consequences. Mitochondria and lysosomes are long known to be fundamental for cellular metabolism. In addition to being energy ‘factories’, mitochondria are key cellular signaling platforms, contributing to cellular stress responses like autophagy, apoptosis or cell proliferation. Lysosomes have evolved beyond their ‘waste management’ roles and are now understood to coordinate major processes such as autophagy and nutrient sensing. Although for many years, these organelles were seen as independent functional entities in the cell, recent evidence suggests the existence of functional interdependent networks between lysosomes and mitochondria. In this study, we elucidate mechanisms beyond autophagy of crosstalk between lysosomes and mitochondria, and show that lysosomal defects affect mitochondrial function.
To identify mechanisms regulating lysosomal and mitochondrial crosstalk, we employed two distinct models of lysosomal storage disorders (LSDs): Niemann-Pick disease and Pompe’s disease. We evaluated the effects of chronic lysosomal malfunction in these models on mitochondrial fitness and function.
We showed in patient cells of Niemann-Pick disease that impaired S1P signaling engages transcriptional programs, via KLF2 and ETV1, to repress mitochondrial biogenesis and function. In support of these findings, in silico analyses on microarray datasets of brain and liver samples of NPC1-/- mice confirmed the repression of mitochondrial biogenesis and the induction of KLF2 and ETV1. Interestingly, mechanisms of KLF2 and ETV1 downregulation, including siRNA-mediated silencing and enhanced S1P signaling, are sufficient to promote mitochondrial biogenesis in Niemann-Pick disease. These findings uncover the involvement of a transcriptional network in the regulation of lysosomal and mitochondrial crosstalk and the therapeutic potential of modulating S1P signaling in Niemann-Pick disease.
In the acid alpha-glucosidase (GAA) knockout mouse model, a model for the human Pompe’s disease, we showed extensive mtDNA defects in various tissues and cells. Interestingly, loss of mtDNA was independent of mitochondrial biogenesis. Rather, we demonstrated that mtDNA depletion was dependent on reduced nucleotide bioavailability. Strikingly, mtDNA depletion could be reversed by enhanced nucleotide biosynthesis through folate supplementation. Furthermore, this study demonstrated that impaired iron homeostasis, which affected the activity of iron-containing proteins including respiratory chain complex IV and ribonucleotide reductases among others, was culpable for reduced nucleotide bioavailability and mtDNA depletion. In addition, mtDNA defects were associated with induction of the innate immune response via TLR9-mediated signaling in GAA-/- mouse tissues, which culminates in gliosis in the cortex. Strikingly, iron supplementation reverses mtDNA defects in MEFs and in the cortex of GAA knockout mice and dampens pro-inflammatory signaling in the cortex.
Altogether, the findings of this study demonstrate that lysosomal malfunction has detrimental consequences for mitochondrial fitness and function, both in vitro and in vivo, and elucidate novel mechanisms of lysosomal and mitochondrial interplay. In addition, this study shows that the mechanisms of organelle crosstalk could provide therapeutic avenues for LSDs and even for neurodegenerative diseases (e.g., Parkinson’s disease). | de |