Abstract
The balanced functionality of cellular proteostatic modules is central to both proteome stability and mitochondrial physiology; thus, the age-related decline of proteostasis also triggers mitochondrial dysfunction, which marks multiple degenerative disorders. Non-functional mitochondria are removed by mitophagy, including Parkin/Pink1-mediated mitophagy. A common feature of neuronal or muscle degenerative diseases, is the accumulation of damaged mitochondria due to disrupted mitophagy rates. Here, we exploit Drosophila as a model organism to investigate the functional role of Parkin/Pink1 in regulating mitophagy and proteostatic responses, as well as in suppressing degenerative phenotypes at the whole organism level. We found that Parkin or Pink1 knock down in young flies modulated proteostatic components in a tissue-dependent manner, increased cell oxidative load, and suppressed mitophagy in neuronal and muscle tissues, causing mitochondrial aggregation and neuromuscular degeneration. Concomitant to Parkin or Pink1 knock down cncC/Nrf2 overexpression, induced the proteostasis network, suppressed oxidative stress, restored mitochondrial function, and elevated mitophagy rates in flies’ tissues; it also, largely rescued Parkin or Pink1 knock down-mediated neuromuscular degenerative phenotypes. Our in vivo findings highlight the critical role of the Parkin/Pink1 pathway in mitophagy, and support the therapeutic potency of Nrf2 (a druggable pathway) activation in age-related degenerative diseases.
Highlights
Mitochondria are very dynamic organelles as they change their shape, size, and sub-cellular localization depending on the versatile cellular demands for adequate ATP production, optimal cellular function, and survival [1]
UPP and ALP play a critical role in regulating cellular functionality and viability and the decline of their activity is a hallmark of aging, and of multiple age-related diseases including neuromuscular degenerative disorders [16, 32]
We report that park or Pink1 KD in young flies modulated proteostatic modules in a tissue-dependent manner; ubiquitously increased cell oxidative load, and suppressed mitophagy in neuronal and muscle tissues causing mitochondrial aggregation and neuromuscular degeneration
Summary
Mitochondria are very dynamic organelles as they change their shape, size, and sub-cellular localization depending on the versatile cellular demands for adequate ATP production, optimal cellular function, and survival [1]. A common feature of neurodegenerative conditions such as Parkinson’s (PD) and Alzheimer’s (AD) disease is mitochondria dysfunction [2, 3]. The maintenance of cellular mitostasis directly correlates with mitochondria quality control, which is driven by mitochondrial dynamics, mitochondrial removal, and biogenesis. A terminal response to mitochondria dysfunction is their selective destruction by mitophagy [5]; a highly conserved process, where damaged mitochondria are removed by autophagosomes and delivered for degradation to lysosomes [6]. Pink is activated by auto-phosphorylation and accumulates on the outer mitochondrial membrane (OMM) of dysfunctional mitochondria triggering the recruitment of the E3 ubiquitin ligase Parkin, which ubiquitinates several proteins of OMM, amplifying a cascade signal that culminates in mitochondrial engulfment by the autophagosome [7,8,9]. Mitophagy disruption is a hallmark of AD [12], further supporting the importance of mitochondria quality control in neurodegeneration
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