Protease-cleaved BID is able to induce multiple mitochondrial dysfunctions, including the release of the inter-membrane space proteins, cristae reorganization, depolarization, permeability transition and generation of reactive oxygen species.
For instance, it will be important to determine whether mitochondrial iron overload occurs in cells from individuals with multiple mitochondrial dysfunctions syndrome caused by mutations in NFU1 or BOLA3 (Cameron et al., 2011) (Table 1).
Finally, two forms of a disease called multiple mitochondrial dysfunctions syndrome, caused by mutations in either NFU1 or BOLA3, indicate that some Fe-S proteins might acquire their clusters from a specific and essential subset of donor proteins (Cameron et al., 2011; Navarro-Sastre et al., 2011).
Biallelic mutations in IBA57, encoding a Fe/S mitochondrial protein assembly factor, can be responsible for a slowly progressive childhood-onset HSP (Lossos et al. 2015), up to multiple mitochondrial dysfunction syndrome 3 (MMDS3; OMIM #615330), a severe lethal encephalopathy with multiple malformations, myopathy and hyperglycinemia (Ajit Bolar et al. 2013).
55 Furthermore, ectopic DUX4-FL expression has recently been linked to pathology through possibly increased oxidative stress 56; and increased oxidative stress through multiple mechanisms, including mitochondrial dysfunction, is known to lead to impaired protein turnover.
Though the function of frataxin is still partly controversial, there is general agreement that it is involved in cellular iron homeostasis and that its deficiency results in multiple enzyme deficits, mitochondrial dysfunction, and oxidative damage.
Since mitochondria are the powerhouses of the cell and serve as the converging points of multiple metabolic pathways, mitochondrial dysfunction has long been suspected to play a key role in metabolic alterations in cancers.
Mitochondrial dysfunctions occur in several human inherited disorders [20].
Mitochondrial dysfunctions are implicated in AD brains.
Depending on the cell type, death stimulus, and experimental conditions, multiple molecular mechanisms of mitochondrial dysfunction may co-exist involving the cyto c release, permeability transition pore (PTP) complex activity, and the BAX/BAK pore-forming properties [26], [27], [35] in causing the MOMP.
Mitochondrial dysfunction is widely believed to be an early and critical component of multiple neurodegenerative diseases, including AD. Accumulations of A β and τ are both associated with mitochondrial dysfunction at multiple levels.
