IUBMB Life special issue: Mitochondrial biology and the yeast paradigm

Abstract

The study of mitochondrial biogenesis has long been intertwined with the utilization of yeast species as model organisms.¹ The liaison between yeast and mitochondrial research began in the 1950s when Boris Ephrussi first identified Saccharomyces cerevisiae mutants whose respiratory-deficient phenotype was not inherited following Mendelian laws.² Later, the cytosolic genetic element he called the rho factor was identified as the mitochondrial DNA (mtDNA) in yeast and mammalian cells,^{3, 4} laying the foundation for the field of mitochondrial genetics. Experimental work with yeast has continuously fueled pivotal discoveries in mitochondrial biogenesis, contributing to delineating the processes of mitochondrial genome replication and expression, including their unique features like the deviation from the “universal” genetic code.⁵ Pioneering work by Piotr Slominski and Alexander Tzagoloff, who isolated and characterized yeast point mutants in mitochondrial genes (mit⁻) and respiratory deficient nuclear mutants (pet⁻),^6-8 facilitated the identification of mitochondrion-encoded polypeptides and paved the way for investigating their coordinated expression and assembly into functional mitochondrial respiratory complexes of dual genetic origin. These ante litteram large-scale genetic screens seamlessly exemplify the power of yeast as a model organism to study mitochondrial biology. This power is illustrated by the collection of articles presented in this special issue.

The aerobe-anaerobe facultative metabolism of S. cerevisiae and its life cycle, allowing for the analysis of individual meiotic event products, have enabled the isolation and study of mutants with compromised or null respiratory capacity. Over the past five decade, the work of numerous yeast laboratories has focused on elucidating the structure, function, and biogenetic pathways of the enzymes of the mitochondrial respiratory chain and oxidative phosphorylation (OXPHOS) system. These studies have spanned all aspects of OXPHOS biogenesis, from the early assembly step of highly hydrophobic mitochondrion-encoded catalytic subunits, described by Jung et al.,⁹ to the organization of individual respiratory complexes into supercomplexes, the function/s and biogenesis of which are discussed by Eldeeb et al.¹⁰ Moreover, elucidating highly conserved pathways such as mitochondrial protein import and metabolite transport, to name a few, has largely benefited from the extensive array of genetics and biochemical tools available to yeast researchers.¹¹ Notably, thanks to its efficiency in mitochondrial homologous recombination, S. cerevisiae is one of the two only organisms where genetic transformation of mitochondria can be achieved through the bombardment of DNA-coated metal microbeads, a technique known as biolistic transformation. The impact of this approach on the study of mitochondrial biogenesis and energetic metabolism is discussed by Veloso R. Franco et al.¹²

Undoubtedly, yeast has been instrumental in uncovering fundamental biological processes that are conserved across evolution. In her review, Dieckmann¹³ focuses on the fatty acids and lipoic acid biosynthetic pathways and their recently described links to mitochondrial translation thus far in patients and iron–sulfur cluster biogenesis. Remarkably, approximately 70% of nuclear genes involved in human mitochondrial disorders are conserved in S. cerevisiae.¹⁴ Key examples are represented by the mtDNA polymerase POLG, and the ADP/ATP carrier Aac2/ANT1. More than 300 pathogenic mutations in POLG have been identified suffering from mitochondrial disorders characterized by mtDNA multiple deletions/depletion. Gilea et al.¹⁵ discuss the use of S. cerevisiae as a platform for assessing mutation pathogenicity, delineating biochemical and physiological consequences, and conducting screenings for compounds with potential therapeutic efficacy. Moreover, Mishra et al.¹⁶ review the important contribution of yeast models to our understanding of the pathogenic mechanisms underlying dominant pathogenic mutations in the mitochondrial ADP/ATP carrier, including the discovery of the Precursor Overaccumulation Stress (mPOS) pathway.

Furthermore, critical insights have also been gathered from non-conventional yeast species, such as Schizosaccharomyces pombe, whose metabolism and mitochondrial genome bear closer resemblance to those of mammalian cells.¹⁷ Unlike budding yeast, S. pombe contains a compacted mtDNA that, akin to human cells, is transcribed into three long polycistronic transcripts that are subsequently processed following the tRNA punctuation model. The different aspects of mitochondrial gene expression in fission yeast are comprehensively described by Dinh et al.,¹⁸ who placed a specific emphasis on the process of mitochondrial translation and the numerous factors involved. Conversely, differences in mtDNA organization and RNA biology across species have provided insights into evolutionary mechanisms and how diverse organisms have addressed similar challenges. In his review, Golik¹⁹ describes the mitochondrial transcriptome of S. cerevisiae and its biology and highlights the rapid evolution and resulting diversity of the mitochondrial genome and gene expression system amongst budding yeasts.

Mitochondria are not an isolated entity within eukaryotic cells, and during evolution, these ancestral endosymbiotic bacteria have developed extensive physical connections with other cellular organelles and a wide network of signaling pathways. Bui et al.²⁰ delineate the mitochondrial retrograde signaling (RTG) pathway, which controls nuclear gene expression in response to the functional state of mitochondria. Additionally, numerous pathways have emerged in recent years that mediate mitochondrial protein quality control and maintain homeostasis. Two reviews focus on these surveillance mechanisms: Roedl et al.²¹ examine the role of the proteosome in the recently described mitochondria-associated degradation (MAD) pathway, while Yang et al.²² discuss the interplay between mitochondrial protein quality control and the segregation of mitochondria during cell division.

In summary, this IUBMB Life special issue aims to highlight the contributions of yeast model systems to the study of mitochondrial biology, provide a critical review of the latest developments in yeast research within the field of mitochondrial function and biogenesis, and identify remaining open questions to address in the future of yeast mitochondrial research.