NB the bulk of this was written in 2017, hence the references are a little old

Neurons are especially affected by mitochondrial dysfunction, not just because they have high energy demands, but also long axonal processes which make mitochondrial trafficking particularly important.

Age is the main risk factor for neurodegenerative disease. Mitochondrial involvement can be explained by the oxidative damage model of aging. ROS production from normal mitochondrial activity leads to mtDNA damage and is thought to contribute to cell death by reducing ATP production, reducing mitochondrial membrane potential. This promotes mPTP opening.

In aging, fusion/fission balance favours fission. Fusion… 

Defects in protective mechanisms against reactive oxygen species have been linked to neurodegenerative diseases. Superoxide dysmutase 1 (SOD1), which converts O2• to H2O2, has been linked to amyotrophic lateral sclerosis. Friedrich ataxia has been linked with lower levels of frataxin (Puccio et al 2000), a protein that could detoxify ROS by activation of glutathione peroxidase (Shoichet et al 2002). Frataxin also targets the mitochondria and over-expression leads to increased mitochondrial membrane potential and oxidative phosphorylation (Ristow et al 2000). 

The pathogenesis of Parkinson's disease demonstrates the impact of mitochondrial dysfunction. MPTP is a parkinsonism-inducing toxin. It is monoamine oxidase to MPP+, a Complex I inhibitor (Vyas et al 1986). Neuroleptics can also induce parkinsonism and were found to be potent Complex I inhibitors (Burkhardt et al 1993). Parkinson's disease-associated Complex I defects were investigated by mitochondrial gene transfer experiments, in which human cell cultures were depleted of mtDNA by ethidium bromide, and mtDNA reintroduced by PEG mediated fusion of control platelets or platelets expressing PD complex I defect (Parker and Swerdlow 1998), creating cytoplasmic hybrids ("cybrids"). PD cybrids showed significant loss of complex I activity. Some ROS-metabolising species are also upregulated in PD cybrids (Cassarino et al 1997), suggesting excess production of ROS. 

Selective mitophagy and fission allow damaged mitochondria with lower membrane potential to be preferentially degraded. One of the genes that regulates this is PARK2, which codes for Parkin. It is ubiquitously expressed and has E3 ubiquitin ligase activity (Kitada et al 1998). Parkin is recruited and activated by PINK1, a mitochondrial health sensor. Once recruited, Parkin conjugates ubiquitin onto OMM proteins, which triggers a signalling cascade resulting in mitochondrial engulfment by autophagosomes.

In healthy mitochondria, PINK1 is imported to the IMM by translocase and driven by the transmembrane potential. PNK1 is then processed by matrix processing peptidase (MPP) and cleaved by PARL. PARL cleavage exposes the FLO4 amino acid residue, leaving it vulnerable to ubiquitin proteasomal degradation. PINK1 import and degradation is constitutive. 

Damage to mitochondria makes it lose its membrane potential or accumulate unfolded proteins. In this case, PINK1 is not imported to the IMM (Jin et al 2010), but instead accumulates on the OMM where it is autophosphorylated. This s required for its kinase activity and Parkin recruitment.

#physiology #cell-biology