Roles of Metals in Normal Mitochondrial Diseases, Cell Metabolism 2013
"...Neurodegenerative Diseases
The brain needs far more energy than other organs, necessitating optimal ATP production by neurons. Many neurodegenerative diseases are associated with both mitochondrial dysfunction and metal deposition in the vicinity of brain lesions, but in general the pathogenesis is unclear. Several key proteins associated with neurodegenerative diseases have been reported to have intimate connections to transition metals. Amyloid precursor protein (APP) was reported to have an intrinsic ferroxidase activity (Duce et al., 2010), although other investigators have not observed this (Ebrahimi et al., 2012). Alpha-synuclein (SNCA) and prion protein (PRNP) assemble into metal-containing aggregates. Although APP, SNCA, and PRNP are not known to be directly involved in mitochondrial metal metabolism, mitochondrial quality and quality control are strongly implicated in the neurodegenerative diseases with which they are associated.

Neurodegeneration with brain Fe accumulation (NBIA) disorders are distinguished by characteristic Fe accumulation in the basal ganglia visualized by magnetic resonance imaging and obvious brown (Fe) discoloration of the brain on autopsy. The gene most commonly mutated in NBIA, pantothenate kinase 2 (PANK2), encodes an enzyme important for mitochondrial coenzyme A biosynthesis (Zhou et al., 2001). Other genes mutated in NBIA patients include a novel mitochondrial protein, C19orf12, possibly also involved in coenzyme A metabolism (Hartig et al., 2011).

Neurodegeneration with impaired mitochondrial function in motor neurons has been reported in Ireb2-/- mice lacking IRP2 (Jeong et al., 2011). Abnormal cellular Fe homeostasis results in decreased complex I and II activity in the mitochondria of lower motor neurons, apparently because of inappropriate regulation resulting in decreased expression of Tfrc and increased storage of iron in ferritin. Accordingly, the phenotype was ameliorated by a genetic maneuver to decrease ferritin production. Taken together, these results suggest that cellular Fe deficiency can also cause neuronal degeneration.

The gene encoding Cu-Zn SOD1 is mutated in a subgroup of patients with familial amyotrophic lateral sclerosis (ALS), and mitochondrial dysfunction is a common feature of both genetic and sporadic forms of the disease. SOD1 mutations are considered to be gain-of-function, and the mutant protein preferentially accumulates in the mitochondrial intermembrane space. Various models for toxic gain-of-function mutations have been proposed, involving increased production of ROS and Ca2+ dysregulation (for review, see Faes and Callewaert, 2011), but the pathophysiology is still unresolved.

Much remains to be learned about metals, mitochondria, and neurodegenerative diseases. There is substantial overlap in clinical presentation and pathologic features among these disorders, but there is still uncertainty about cause and effect. Does mitochondrial dysfunction lead to metal accumulation, or does metal accumulation lead to ROS production and mitochondrial dysfunction? Are protein-metal aggregates causing mitochondrial dysfunction and neurodegeneration, or are they a marker of neurodegeneration, or both?

Conclusions
The relationship between metals and mitochondria has been studied for decades, but much remains to be learned. Our current understanding relies heavily on elegant studies in yeast and on inborn errors of metabolism in human patients. Fully elucidating the interaction between metals and mitochondria in disease will require new approaches, but it will undoubtedly enrich our understanding of mitochondrial biology..." Learn more: http://www.sciencedirect.com/science/article/pii/S1550413113000521