Hepatic involvement is a common feature in childhood mitochondrial hepatopathies, particularly in the neonatal period. Respiratory chain disorders may present as neonatal acute liver failure, hepatic steatohepatitis, cholestasis, or cirrhosis with chronic liver failure of insidious onset. In recent years, specific molecular defects (mutations in nuclear genes such as SCO1, BCS1L, POLG, DGUOK, and MPV17 and the deletion or rearrangement of mitochondrial DNA) have been identified, with the promise of genetic and prenatal diagnosis. The current treatment of mitochondrial hepatopathies is largely ineffective, and the prognosis is generally poor. The role of liver transplantation in patients with liver failure remains poorly defined because of the systemic nature of the disease, which does not respond to transplantation. Prospective, longitudinal, multicentered studies will be needed to address the gaps in our knowledge in these rare liver diseases. (HEPATOLOGY 2007;45:1555-1565.) S tructural and functional alterations of mitochondria are recognized as being responsible for a growing number of pathologic disorders, affecting the central and peripheral nervous system, skeletal and cardiac muscles, the liver, bone marrow, the endocrine and exocrine pancreas, the kidneys, and the intestines. [1][2][3] Because the liver, with its biosynthetic and detoxifying properties, is highly dependent on adenosine triphosphate (ATP), hepatocytes contain a high density of mitochondria. Disorders affecting mitochondrial oxidative phosphorylation (OXPHOS) have a direct effect on mitochondrial and cellular metabolism, producing steatosis or cholestasis, hepatocyte death, and progressive liver injury. 1,[4][5][6] Mitochondrial hepatopathies occur primarily in early childhood; however, secondary disorders present at any age. Remarkable advances have been made recently in our understanding of mitochondrial hepatopathies, including the identification of the molecular basis of many disorders. The present review focuses on recent advances made in primary mitochondrial hepatopathies, including their genetics and management, and the future directions for research.
Structure, Function, and Genetics of Mitochondria
Mitochondria are double-membrane intracellular organelles and the main source of the high-energy phosphate molecule ATP, which is essential for all active intracellular processes. 1 ATP is produced by the respiratory chain on the inner mitochondrial membrane by OXPHOS (Fig. 1). 1 In this process, electron transfer proteins (NADH [reduced nicotinamide adenine dinucleotide], FADH 2 [reduced flavine adenine dinucleotide]), and electron transfer flavoprotein], which are reduced as a result of the metabolism of carbohydrates, proteins, and lipids, donate electrons to complexes I and II and ubiquinones, which then flow down an electrochemical gradient to ubiquinone complex III, cytochrome c, and finally complex IV, resulting in the active translocation of protons (Hฯฉ) out of the mitochondrial matrix into the intermembrane space, which establishes an electrochemical gradient. At complex V, protons flow back into the mito-