Autophagy is a self-digestive process that degrades intracellular components, including damaged organelles, to maintain energy homeostasis and to cope with cellular stress. Autophagy plays a key role during development and adult tissue homeostasis, and growing evidence indicates that this catalytic process also has a direct role in modulating aging. Although autophagy is essentially protective, depending on the cellular context and stimuli, autophagy outcome can lead to either abnormal cell growth or cell death. The autophagic process requires a tight regulation, with cellular events following distinct stages and governed by a wide molecular machinery. Reactive oxygen species (ROS) have been involved in autophagy regulation through multiple signaling pathways, and mitochondria, the main source of endogenous ROS, have emerged as essential signal transducers that mediate autophagy. In the present review, we aim to summarize the regulatory function of mitochondria in the autophagic process, particularly regarding the mitochondrial role as the coordination node in the autophagy signaling pathway, involving mitochondrial oxidative stress, and their participation as membrane donors in the initial steps of autophagosome assembly.

Hypoxia is a condition characterized by insufficient tissue oxygenation, which results in impaired oxidative energy production. A reduction in cellular oxygen levels induces the stabilization of hypoxia inducible factor α (HIF-1α), master regulator of the molecular response to hypoxia, involved in maintaining cellular homeostasis and driving hypoxic adaptation through the control of gene expression. Due to its high energy requirement, the brain is particularly vulnerable to oxygen shortage. Thus, hypoxic injury can cause significant metabolic changes in neural cell populations, which are associated with neurodegeneration. Recent evidence suggests that regulating HIF-1α may ameliorate the cellular damage in neurodegenerative diseases. Indeed, the hypoxia/HIF-1α signaling pathway has been associated to several processes linked to Parkinson’s disease (PD) including gene mutations, risk factors and molecular pathways such as mitochondrial dysfunction, oxidative stress and protein degradation impairment. This review will explore the impact of hypoxia and HIF-1α signaling on these specific molecular pathways that influence PD development and will evaluate different novel neuroprotective strategies involving HIF-1α stabilization.