Mitochondrial hepatopathies: advances in genetics, therapeutic approaches, and outcomes.

C ellular mitochondria play important roles in the production of energy required by human cells, thermogenesis, calcium and iron homeostasis, innate immune responses, production of reactive oxygen species, and programmed cell death (apoptosis). Approximately 1000 nuclear genes encoding mitochondrial proteins have been identified to date. A mutation in any of these genes has the potential to give rise to monogenic or primary mitochondrial disorders. Mitochondrial dysfunction is also associated with many common human conditions, including cardiac disease, diabetes, cancer, epilepsy, obesity, and degenerative diseases such as Parkinson and Alzheimer’s diseases. A unique feature of mitochondria in mammalian cells is the presence of a separate genome, mitochondrial DNA (mtDNA), which is distinct from nuclear genes. The respiratory chain peptide components are encoded by both nuclear and mtDNA genes. Thirteen essential polypeptides are synthesized from the small (16.5-kb), circular, double-stranded mtDNA, and nuclear genes encode more than 70 respiratory chain subunits and an array of enzymes and cofactors required to maintain mtDNA. Mitochondrial hepatopathies, disorders in which dysfunction of hepatocyte mitochondria plays a key role in the pathogenesis of liver injury or failure, are divided into primary and secondary disorders. Mitochondrial hepatopathies as a whole have been characterized only relatively recently, and the identification of more types is anticipated. Primary mitochondrial hepatopathies occur when a mitochondrial protein, transfer RNA, or ribosomal RNA is miscoded by a mutation in either a nuclear gene or an mtDNA gene. Secondary mitochondrial hepatopathies are conditions in which mitochondria are the targets of endogenous or exogenous toxins. Examples include Reye syndrome, copper and iron overload conditions, drugs (eg, salicylates, reverse-transcriptase inhibitors, antimycin A) and toxins (eg, ethanol, cyanide), cholestasis, nonalcoholic steatohepatitis, and a-1 antitrypsin deficiency. In primary mitochondrial hepatopahies, liver involvement is often part of multiorgan manifestations (Table I). Much of our current knowledge about mitochondria has come from studying patients with respiratory chain disorders, which compose a growing number of individually