Mitochondrial-associated metabolic disorders: foundations, pathologies and recent progress

Abstract

Research in the last decade has revolutionized the way in which we view mitochondria. Mitochondria are no longer viewed solely as cellular powerhouses; rather, mitochondria are now understood to be vibrant, mobile structures, constantly undergoing fusion and fission, and engaging in intimate interactions with other cellular compartments and structures. Findings have implicated mitochondria in a wide variety of cellular processes and molecular interactions, such as calcium buffering, lipid flux, and intracellular signaling. As such, it does not come as a surprise that an increasing number of human pathologies have been associated with functional defects in mitochondria. The difficulty in understanding and treating human pathologies caused by mitochondrial dysfunction arises from the complex relationships between mitochondria and other cellular processes, as well as the genetic background of such diseases. This review attempts to provide a summary of the background knowledge and recent developments in mitochondrial processes relating to mitochondrial-associated metabolic diseases arising from defects or deficiencies in mitochondrial function, as well as insights into current and future avenues for investigation.

Figure 1

The mitochondrial life cycle. Since mitochondria cannot be synthesized de novo, they must arise from existing mitochondria. Mitochondrial biogenesis is the process by which mitochondria increase in size, accompanied by lipid synthesis and assembly of ETC subunits. One mitochondrion can divide into two physically distinct mitochondria by the process of fission, which requires the mechanical force of the ER and the Drp1 protein, which is recruited to mitochondria by the Mff receptor. Two mitochondria can also join together to become one mitochondrion with continuous inner- and outer-membranes in a process termed mitochondrial fusion, which requires the proteins Mfn1, Mfn2, and OPA1. In the case of mitochondrial damage, indicated by decreased ETC activity, oxidizing membrane potential, and accumulation of ROS and unfolded proteins, a mitochondrion may be degraded by mitophagy. The marking of mitochondria for degradation is facilitated by the NIX/LC3 pathway during erythrocyte differentiation, and by the Pink1/Parkin pathway in other cell types.

Figure 2

ER and mitochondria interact intimately to perform cellular functions. (A) ER-mitochondria contact sites mediate a variety of processes. ER-mitochondria contact sites are sites of lipid and calcium exchange, used for modifying membrane lipids and sequestering calcium ions for modulating mitochondrial function as targets of intracellular signaling cascades. Such contact sites are also thought to be regulators of mitochondrial fission in a recent hypothesis that holds that ER extensions aid in the recruitment of Mff and Drp1 to mitochondria, and furthermore provide mechanical force for fission. Additionally, recent findings show that the ER and mitochondria are inherited in a co-dependent manner in yeast, facilitated by the Mmr1 protein, which binds mitochondria to cortical ER sheets in the yeast bud tip. (B) In response to an external stimulus indicating cellular stress, calcium ions sequestered in the ER lumen are released into the cytosol by the transmembrane inositol 1,4,5-triphosphate receptor protein. Released calcium ions then enter ER-tethered mitochondria by an unknown transmembrane calcium channel located in the outer mitochondrial membrane, followed by translocation into the mitochondrial matrix by the mitochondrial calcium uniporter. The targets of calcium ions in the matrix primarily include energy-producing processes, but can also lead to apoptosis in cases of severe cellular stress.

Figure 3

Mutations affecting oxidative phosphorylation are the foundation of mitochondrial-associated metabolic disorders. Mutations (red) in genes critical for mitochondrial processes (green) lead to mitochondrial-associated diseases (blue). Human mtDNA encodes 13 proteins (including subunits of ETC complexes) and 22 tRNAs on a circular genome. A D-loop region is the site of mtDNA polymerase gamma binding. Mutations within the D-loop region, or in the POLG gene, lead to defects in mtDNA replication and eventually mtDNA depletion. In the case of MNGIE, mutations in the nuclear TYMP gene, which encodes a protein involved in nucleotide synthesis, also lead to defects in mtDNA replication due to an unbalanced nucleotide pool. Mitochondria that have no mtDNA copies can no longer synthesize ETC subunits encoded by the mtDNA, leading to defects in oxidative phosphorylation. In another example of a mutation in a nuclear gene affecting mitochondrial function, mutations in genes encoding proteins required for CoQ synthesis lead to CoQ deficiency and therefore defects in electron transfer in the ETC, resulting in defects in oxidative phosphorylation. Finally, mutations in mtDNA genes themselves, including genes encoding ETC subunits or tRNAs essential for mitochondrial gene expression, lead to defects in the synthesis of ETC protein subunits or non-functional complexes. Such mutations comprise the majority of mutations associated with mitochondrial-associated diseases (excluding POLG mutations), and have been associated with lactic acidosis, MELAS, and mitochondrial myopathies.