Mitophagy pathway

Mitophagy is the selective degradation of mitochondria by autophagy. It often occurs to defective mitochondria following damage or stress. The term was coined by J.J. Lemasters in 2005.[1] Mitochondrial fragments had been seen in liver lysosomes as early as 1962,[2] and a 1977 report suggested that “mitochondria develop functional alterations which would activate autophagy”.[3]

Mitophagy is key in keeping the cell healthy. It promotes turnover of mitochondria and prevents accumulation of dysfunctional mitochondria which can lead to cellular degeneration.

It is mediated by Atg32 (in yeast) and NIX and its regulator BNIP3 in mammals. Mitophagy is regulated by PINK1 and parkin proteins. In addition to the selective removal of damaged mitochondria, mitophagy is also required to adjust mitochondrial numbers to changing cellular metabolic needs, for steady-state mitochondrial turnover, and during certain cellular developmental stages, such as during cellular differentiation of red blood cells.[4]

Organelles and bits of cytoplasm are sequestered and targeted for degradation by the lysosome for hydrolytic digestion by a process known as autophagy. Mitochondria metabolism leads to the creation of by-products that lead to DNA damage and mutations. Therefore, a healthy population of mitochondria is critical for the well-being of cells. Previously it was thought that targeted degradation of mitochondria was a stochastic event, but accumulating evidence suggest that mitophagy is a selective process.[5]

Generation of ATP by oxidative phosphorylation leads to the production of various reactive oxygen species (ROS) in the mitochondria, and submitochondrial particles. Formation of ROS as a mitochondrial waste product will eventually lead to cytotoxicity and cell death. Because of their role in metabolism, mitochondria are very susceptible to ROS damage.

Damaged mitochondria cause a depletion in ATP and a release of cytochrome c, which leads to activation of caspases and onset of apoptosis. Mitochondrial damage is not caused solely by oxidative stress or disease processes; normal mitochondria will eventually accumulate oxidative damage hallmarks overtime, which can be deleterious to mitochondria as well as to the cell. These faulty mitochondria can further deplete the cell from ATP, increase production of ROS, and release proapoptopic proteins such as caspases.

Because of the danger of having damaged mitochondria in the cell, the timely elimination of damaged and aged mitochondria is essential for maintaining the integrity of the cell. This turnover process consists of the sequestration and hydrolytic degradation by the lysosome, a process also known as mitophagy.

Mitochondrial depletion reduces a spectrum of senescence effectors and phenotypes while preserving ATP production via enhanced glycolysis.[6]

Pathways[edit]

In mammals[edit]

There are several pathways by which mitophagy is induced in mammalian cells.

Cancer[edit]

In 1920 Otto Warburg observed that certain cancerous tumors display a metabolic shift towards glycolysis. This hypothesis is referred to as the “Warburg effect“, in which cancer cells produce energy via the conversion of glucose into lactate, even in the presence of oxygen (aerobic glycolysis). Despite nearly a century since it was first described, a lot of questions remained unanswered regarding the Warburg effect. Initially, Warburg attributed this metabolic shift to mitochondrial dysfunction in cancer cells. Further studies in tumor biology have shown that the increased growth rate in cancer cells is due to an overdrive in glycolysis (glycolytic shift), which leads to a decrease in oxidative phosphorylation and mitochondrial density. As a consequence of the Warburg effect, cancer cells would produce large amounts of lactate. The excess lactate is then released to the extracellular environment which results in a decrease in extracellular pH. This micro-environment acidification can lead to cellular stress, which would lead to autophagy. Autophagy is activated in response to a range of stimuli, including nutrient depletion, hypoxia, and activated oncogenes. However, it appears that autophagy can help in cancer cell survival under conditions of metabolic stress and it may confer resistance to anti-cancer therapies such as radiation and chemotherapy. Additionally, in the microenvironment of cancer cells, there is an increase in hypoxia-inducible transcription factor 1-alpha (HIF1A), which promotes expression of BNIP3, an essential factor for mitophagy.[18]

^ Kanki, T; et al. (2009). “Atg32 is a mitochondrial protein that confers selectivity during mitophagy”. Dev Cell. 17: 98–109. doi:10.1016/j.devcel.2009.06.014.

References[edit]

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Vives-Bauza, C; Przedborski, S (2011). “Mitophagy: the latest problem for Parkinson’s disease”. Trends Mol Med. 17: 158–65. doi:10.1016/j.molmed.2010.11.002.

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Pavlides, S; et al. (2012). “Warburg Meets Autophagy: Cancer-Associated Fibroblasts Accelerate Tumor Growth and Metastasis via Oxidative Stress, Mitophagy, and Aerobic Glycolysis”. Antioxidants & Redox Signaling. 16: 1264–1284. doi:10.1089/ars.2011.4243.

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Valente, EM; Abou-sleiman, PM; Caputo, V; et al. (2004). “Hereditary early-onset Parkinson’s disease caused by mutations in PINK1”. Science. 304 (5674): 1158–60. doi:10.1126/science.1096284. PMID 15087508.

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