Molecular bases of mitochondrial disorders.

Abstract

Maintaining the health of the human population depends on integrative strategies, which include both prevention and therapeutics. A detailed understanding of the processes and reactions occurring in our bodies and cells, especially at the molecular level, is a prerequisite to understanding the links between disease and dysfunctions of molecular mechanisms regulating (inter)cellular processes, and to design successful therapies against diseases. Mitochondria host diverse metabolic pathways and are key to cellular energy conversion. Therefore, they are considered the ‘power houses’ of eukaryotic cells. In addition to these central metabolic functions, we are beginning to appreciate that mitochondria are also central signaling hubs that are deeply integrated into cellular communication pathways [[1, 2]]. Given the broad importance of mitochondria for cellular homeostasis, it is not surprising that mitochondria have been directly or indirectly linked to a plethora of human disorders. Among these are the large group of mitochondrial disorders caused by mitochondrial dysfunction. Such disorders mostly present with neuromuscular or neurocardiac phenotypes [[3-5]]. However, little is understood about what connects these molecular dysfunctions to the responses and phenotypes observed in diseased cells and in patients. This special issue of FEBS Letters is entitled ‘Molecular bases of mitochondrial disorders’ showcases eleven reviews that present a broad view of our current understanding of how molecular processes are connected with mitochondria physiology and how their dysfunction is linked to diseases. Most mitochondrial functions are executed by proteins, which are of dual genetic origin. The proteome of this important cellular compartments consists mostly of proteins that are nuclear-encoded and synthesized by cytosolic ribosomes, and a small amount of mitochondrial-encoded proteins translated within mitochondria. The mitochondrial genome codifies 2 rRNAs, 22 tRNAs, and 11 mRNAs, which give rise to thirteen polypeptides. All of these proteins are constituents of the oxidative phosphorylation system (OXPHOS) in the inner mitochondrial membrane and thus are key to cellular energy supply. Approximately a quarter of the mitochondrial proteome is dedicated to the maintenance and expression of the mitochondrial genome and thereby contributes to the ability of mitochondria to carry out ATP production. In order to form functional enzyme complexes of the OXPHOS, the mitochondrial-encoded proteins need to engage with structural subunits imported into mitochondria from the cytosol. In this regard, four reviews in this special issue address mitochondrial gene expression processes and assembly of the OXPHOS in the context of mitochondrial disorders. Filograna et al. al discuss the current knowledge of the copy number of mitochondrial DNA molecules in different human diseases, such as mitochondrial disorders, neurodegenerative disorders, and cancer, as well as in the aging process [[6]]. Richter et al. focus on mitochondrial tRNA variants that are affected in mitochondrial diseases [[7]]. The mitochondrial ribosome and how its dysfunction is linked to human disease are addressed in the review by Ferrari et al. [[8]]. An article by Fernandez-Vizarra et al. provides a detailed account of the history and current views on clinical phenotypes and the molecular pathology of disorders of the OXPHOS system [[9]]. In order to respond to the physiological needs of the cell, mitochondria must be dynamic and plastic in terms of their structure and proteome. Hence, protein homeostasis represents a central regulatory switchboard for integrating mitochondrial function and mitochondrial communication. In this context, we have learned that the import of mitochondrial proteins can be modulated through diverse signaling pathways and that gene expression does indeed respond to the efficiency of protein influx from the cytosol at various levels, including gene transcription and protein translation [[10-12]]. This understanding would not be possible without an amazing progress in technology that has paved the way to ‘omics’ approaches. These technologies do not only deepen our knowledge of the biology of mitochondria but also provide a better understanding of their pathology, both in general manner and in a personalized manner. An interesting example of how new sequencing technologies have broadened our view on mitochondrial disorders is the identification of patients with mutations in transport machinery subunits, which mediate the transport of nuclear-encoded proteins into mitochondria. Interestingly, while it was long considered that defects in protein translocase subunits would not be compatible with life based on the evidence provided by model organisms, an increasing number of patients with defects in protein transport processes have been identified in recent years [[13]]. This raises exciting new questions on the cellular and organismal responses that allow cells to deal with protein import deficiencies in a pathological context. In addition, this example also shows how important the new technical approaches are to define the genetic cause of mitochondrial disorders in patients. Along these lines, the article by Gusic et al. highlights the genetics underlying mitochondrial disorders [[14]]. The function of the OXPHOS system is intimately linked to the mitochondrial ultrastructure. OXPHOS complexes are located in the cristae of the inner mitochondrial membrane. This organization is important for the generation of the proton gradient that drives ATP synthesis. In return, the protein complexes of the OXPHOS participate in shaping this membrane. We are only beginning to understand how lipid biogenesis and protein machineries cooperate in organizing mitochondrial membranes. Yet, a key player in this process is the MICOS complex, which is required for the region with high membrane curvature that links the cristae to the inner boundary membrane, referred to as cristae junction, to attain its characteristic shape. This topic is at the heart of a review by Mukherjee et al., who discuss how the inner mitochondrial membrane is shaped and how dysfunction of the MICOS complex is linked with human disorders [[15]]. Of similar importance for mitochondrial function are mitochondrial network dynamics. Mitochondria undergo constant fission and fusion processes; this allows cells to remodel their mitochondrial network in response to metabolic challenges or external insults. The review by Yapa et al. describes that mitochondrial dynamics are at the heart of cellular physiology and highlights how dysregulation of the fission and fusion machineries leads to human disorders [[16]]. In addition to supplying mitochondria with proteins, cells have developed elaborated quality control systems to surveille and react to the functional status of mitochondria. On the one hand, this relates to proteome adaptation through import and gene expression and, on the other hand, to protein quality control processes [[17]]. Gomez-Fabra et al. evidence how mitochondrial proteases are integrated into human mitochondrial (dys)function [[18]], while Krämer et al. highlight the role of the cytosolic proteolytic system in the quality control of mitochondrial precursor proteins [[19]]. Remarkably, such a cellular control system does not only deal with proteins at various levels, but also deal with mitochondria as a whole. These elaborate and strongly regulated pathways have evolved to ensure that non- or subfunctional mitochondria are disposed through mitophagy, one of the cellular autophagy pathways. This process and its pathological alterations are reviewed by Onishi and Okamoto in this issue [[20]]. In addition, the authors discuss the molecular mechanisms whereby the functional status of mitochondria is intertwined with the overall metabolic plasticity of the cell [[20]]. In summary, insights into the basic features of mitochondria, their function, form, and regulatory integration, are critical for understanding mitochondrial diseases. Given the broad importance of mitochondrial function for cell’s physiology, it is not surprising that all of these processes contribute to age-related degenerative disorders and cancer. Accordingly, mitochondrial research is central to understanding cellular homeostasis and pathologic processes and will remain so for years to come. Agnieszka Chacinska is a professor at the University of Warsaw and director of a newly established institute of Polish Academy of Sciences (PAS), International Institute of Molecular Mechanisms and Machines. She received her PhD from the Institute of Biochemistry and Biophysics PAS and postdoctoral training, followed by a group leader position at the University of Freiburg (Germany). In 2009, she established the Laboratory of Mitochondrial Biogenesis at the International Institute of Molecular and Cell Biology in Warsaw. She and her group moved to the University of Warsaw in 2017. She is a member of Polish Academy of Sciences, EMBO, and Academia Europaea. Her current research concerns the links between mitochondrial protein import and biogenesis with cellular homeostasis, and their role in health and disease. Peter Rehling is a professor and director of the Department of Cellular Biochemistry at the University Medical Center Göttingen and a research fellow at the Max-Planck Institute for Biophysical Chemistry in Göttingen. He studied biology and chemistry at the Ruhr-University Bochum (Germany), where he also received his Ph.D. He worked on protein trafficking processes as a postdoctoral researcher at the Howard Hughes Medical Institute, University of California, San Diego (USA). He then joined the University of Freiburg as an independent researcher, where he and his group focused on mitochondrial protein transport processes. He is a member of German Academy of Sciences (Leopoldina) and Academia Europaea. His current research focuses on mitochondria disorders and protein biogenesis processes, especially mitochondrial gene expression and protein transport.