The role of mitophagy in the regulation of mitochondrial energetic status in neurons

Mitochondria are the main cellular energy powerhouses and supply most of the energy in the form of ATP to fuel essential neuronal functions through oxidative phosphorylation (OXPHOS). In Alzheimer disease (AD), metabolic and mitochondrial disruptions are an early feature preceding any histopathological and clinical manifestations. Mitochondrial malfunction is also linked to synaptic defects in early AD. Mitophagy serves as a key cellular quality control mechanism involving sequestration of damaged mitochondria within autophagosomes and their subsequent degradation in lysosomes. However, it remains largely unknown whether mitophagy is involved in the regulation of energy metabolism in neurons, and if so, whether metabolic deficiency in AD is attributed to mitophagy dysfunction. Here we reveal that mitophagy is broadly activated in metabolically enhanced neurons upon OXPHOS stimulation, which sustains high energetic activity by increasing mitochondrial turnover and hence facilitating mitochondrial maintenance. Unexpectedly, in AD-related mutant HsAPP Tg mouse brains, early stimulation of OXPHOS activity fails to correct energy deficits but exacerbates synapse loss as a consequence of mitophagy failure. Excitingly, lysosomal enhancement in AD neurons restores impaired metabolic function by promoting elimination of damaged mitochondria, protecting against synaptic damage in AD mouse brains. Taken together, we propose a new mechanism by which mitophagy controls bioenergetic status in neurons, furthering our understanding of the direct impact of mitophagy defects on AD-linked metabolic deficits and shedding light on the development of novel therapeutic strategies to treat AD by the early stimulation of mitochondrial metabolism combined with elevation of lysosomal proteolytic activity.

Automated summary

Mitochondria are crucial for supplying energy to neurons, and dysfunction in these organelles is associated with early features of Alzheimer's disease (AD). In AD, metabolic and mitochondrial disruptions occur before clinical symptoms, and mitophagy, a process of clearing damaged mitochondria, plays a role in maintaining energy metabolism and synaptic function. However, in AD mouse models, early stimulation of mitochondrial activity can worsen synaptic loss due to impaired mitophagy. Enhancing lysosomal function restores metabolic function and protects against synaptic damage in AD. This research suggests that targeting mitophagy and lysosomal activity may offer potential therapeutic strategies for AD.