[1] Ashford and Porter used electron microscopy to observe mitochondrial fragments in liver lysosomes by 1962,[2] and a 1977 report suggested that "mitochondria develop functional alterations which would activate autophagy.
[4] Organelles and bits of cytoplasm are sequestered and targeted for degradation by the lysosome for hydrolytic digestion by a process known as autophagy.
Previously it was thought that targeted degradation of mitochondria was a stochastic event, but accumulating evidence suggest that mitophagy is a selective process.
[6] Generation of ATP by oxidative phosphorylation leads to the production of various reactive oxygen species (ROS) in the mitochondria, and submitochondrial particles.
Damaged mitochondria cause a depletion in ATP and a release of cytochrome c, which leads to activation of caspases and onset of apoptosis.
These faulty mitochondria can further deplete the cell of ATP, increase production of ROS, and release proapoptopic proteins such as caspases.
Mitochondrial depletion reduces a spectrum of senescence effectors and phenotypes while preserving ATP production via enhanced glycolysis.
[10] Mitophagy can also be artificially introduced by a series of synthetic autophagy receptors[13] that are composed of antibody fragments to recognize the mitochondrial outer membrane proteins.
[14] In neurons, mitochondria are distributed unequally throughout the cell to areas where energy demand is high, like at synapses and Nodes of Ranvier.
[16] Mitophagy in the nervous system may also occur transcellularly, where damaged mitochondria in retinal ganglion cell axons can be passed to neighboring astrocytes for degradation.
After performing a screen for genes that regulate longevity, it was found in ΔUTH1 strains that there was an inhibition of mitophagy, which occurred without affecting autophagy mechanisms.
Whether these proteins work in concert, are main players in mitophagy, or members in a larger network to control autophagy still remains to be elucidated.
Mitophagy impaired due to the deletion of autophagy-related genes led to a loss of HSC function, more likely as a result of mitochondrial damage that stimulated excessive ROS production.
On the contrary, mitophagy induction appeared to be protective for HSC and directed stem cell differentiation to the myeloid lineage.
It is also important to mention that mitophagy impairment in macrophages is quite common in the early stages of different pathological states.
Consequently, the frequency of regulatory profibrotic M2 macrophages was higher, confirming the role of mitophagy in the induction of the pro-inflammatory M1 phenotype.
[24][25] Many studies demonstrate that the release of mtROS and mtDNA as DAMPs plays a crucial role in the activation of the inflammasome and following inflammation mediated by IL-1β.
[26] The importance of mitophagy was demonstrated by the deletion of Beclin 1 and LC3b autophagy-associated genes in bone marrow-derived macrophages (BMDM).
Defective mitophagy and accumulation of damaged mitochondria led to enhanced mtROS production and the release of cytosolic mtDNA.
[26] Recently, it was shown that Parkin deficiency also triggered NLRP3 activation in a mtROS-dependent manner and as a result promoted viral clearance.
[21][27] Furthermore, Pink1 and Parkin deficiency in a model of polymicrobial sepsis induced inflammasome activation and appeared to be critical in host protection.
It is known that some viruses can modulate mitophagy (directly or indirectly) using different mechanisms and, as a result, cause a disbalance in the innate immune response.
There are specific proteins produced by HPIV3 that induce mitophagy in the infected cell, thus promoting MAVS degradation and the corresponding inhibition of IFN I production.
This 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).
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.
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.
[35] Parkinson's disease is a neurodegenerative disorder pathologically characterized by death of the dopamine-producing neurons in the substantia nigra.
[9] Loss of function in either of these genes results in the accumulation of damaged mitochondria, and aggregation of proteins or inclusion bodies – eventually leading to neuronal death.
Elicited NIX/BNIP3L receptor recruitment of LC3 molecules mediating formation of phagophore that engulf defective mitochondria directly.