Human Mitochondrial Pathologies of the Respiratory Chain and ATP Synthase: Contributions from Studies of Saccharomyces cerevisiae

Abstract

The ease with which the unicellular yeast Saccharomyces cerevisiae can be manipulated genetically and biochemically has established this organism as a good model for the study of human mitochondrial diseases. The combined use of biochemical and molecular genetic tools has been instrumental in elucidating the functions of numerous yeast nuclear gene products with human homologs that affect a large number of metabolic and biological processes, including those housed in mitochondria. These include structural and catalytic subunits of enzymes and protein factors that impinge on the biogenesis of the respiratory chain. This article will review what is currently known about the genetics and clinical phenotypes of mitochondrial diseases of the respiratory chain and ATP synthase, with special emphasis on the contribution of information gained from pet mutants with mutations in nuclear genes that impair mitochondrial respiration. Our intent is to provide the yeast mitochondrial specialist with basic knowledge of human mitochondrial pathologies and the human specialist with information on how genes that directly and indirectly affect respiration were identified and characterized in yeast.

Exploring the Leukemogenic Potential of GATA-1S, the Shorter Isoform of GATA-1: Novel Insights into Mechanisms Hampering Respiratory Chain Complex II Activity and Limiting Oxidative Phosphorylation Efficiency

“…Furthermore, we also demonstrated that GATA-1s over-expression was accompanied by markedly increased levels of SDHC, a subunit of the respiratory chain SQR complex, without any appreciable change in the other three subunits (SDHA, SDHB, SDHD) of the SQR tetramer [6]. In this regard, it is to be noted that, although it has long been assumed that mitochondrial ROS can only be produced at complexes I and III, more recent data pointed out that complex II has a role in ROS production, thus significantly contributing to the mitochondrial control of apoptosis and cell proliferation [12,13,[15][16][17]. In this context, a growing body of research has focused on the role of SDH as a tumor suppressor factor and the relationship between complex II dysregulation and tumorigenesis consequent to chronic ROS elevation and impaired regulation of apoptosis [18,20,21].…”

“…Mitochondria are the main source of intracellular reactive oxygen species (ROS) that are mainly generated at complex I and at complex III of the respiratory chain (RC). The primary ROS produced in mitochondria is superoxide anion (O 2 − ) that can be rapidly converted to hydrogen peroxide by superoxide dismutase (SOD) [12,13]. Notably, although previously largely neglected, more recent data points to a relevant role of complex II, the succinate dehydrogenase (SDH) or succinate-ubiquinone oxidoreductase (SQR) as a key redox regulator of ROS production [14][15][16][17].…”

“…Regarding the heme moiety and the QD site, their significance is still partly unclear. In fact, although the heme b560 is not required for CoQ reduction at the QP site, it supposedly takes part to the assembly of the entire complex in mammalian cells and mediate momentary electron transfer to the low-affinity QD site, thus serving as an electron pocket to avoid interactions between semiquinone CQ and O 2 molecules, potentially leading to uncontrolled ROS generation [12,16,19].…”

Mitochondrial Carriers and Substrates Transport Network: A Lesson from Saccharomyces cerevisiae

“…However, when glucose concentration is very low or when yeast cells grow on non-fermentable carbon sources, energy is produced by respiratory metabolism. Based on these characteristics, yeast is a powerful platform for gaining better understanding of the underlying molecular basis of human diseases [67]. In fact, although human mitochondria are more complex, the high similarity between yeast and human mitochondrial biogenesis and function renders Saccharomyces cerevisiae an excellent model for studying human mitochondrial physiopathology.…”

The ATP Synthase Deficiency in Human Diseases

“…It is therefore possible to distinguish genetic defects caused by (i) alterations in mitochondrial DNA (mtDNA), ∼15%, e.g., Neuropathy, Ataxia, Retinitis Pigmentosa (NARP), Maternally Inherited Leigh's Syndrome (MILS) and Leber's Hereditary Optic Neuropathy (LHON) [5] and (ii) nuclear DNA (nDNA) mutations, which are inherited as Mendelian disorders. A recent review provided an update on the contribution of nuclear genes that impair mitochondrial respiration in patients and have been characterized in yeast [6]. More than 150 distinct genetic mitochondrial dysfunction syndromes characterized by a diminished OXPHOS capacity have been described [5,[7][8][9][10][11].…”