What are the molecular features of inherited human Mitochondrial Disorders?
Can we cure Mitochondrial Disorders?
Mitochondria are the powerhouses of the cell, as they convert most of the energy taken up with nutrient in heat and in a common energy currency of the cell ATP. They key process to perform this essential task for life in virtually all eukaryotes is the ability of the mitochondrial respiratory chain, a group of multiheteromeric enzymes embedded in the inner mitochondrial membrane, to strip off electrons from nutrients (especially carbohydrates, fatty acids and kept acids) to sustain an electron flow that eventually terminates with the reduction of molecular oxygen to water. This process, called respiration, is comparable to an energy producing controlled and stepwise combustion; the energy liberated during respiration is stored by proton pumps intrinsic to respiratory complex I, III and IV, by pumping protons from the inside to the outside of the mitochondrial inner membrane. This electrochemical proton gradient can then be dissipated to produce heart (by uncoupling proteins of mitochondria) or used as a “proton pressure” that promote the movement of a small rotor embedded in the inner mitochondrial membrane, which is connected bean asymmetric stalk to a mobile “cupole” whose “cloves” open and close during the rotation promoting the condensation of ADP and Pi into ATP. The rotation of the rotor and the alternating movements of the cloves are stabilized by a second external stalk called the stator. This is the essential structure of complex V, or mitochondrial ATP synthase, which transducer the energy of respiration into ATP biosynthesis. The entire process, respiration plus ATP synthesis is termed oxidative phosphorylation (OXPHOS). A crucial aspect of OXPHIOS is that the formation of four out of the five canonical multiheteromeric enzymes that form it is dependent on the codification of 13 proteins whose genes are contained in an autonomous genome, spatially and functionally separated from the nuclear genome, present in multiple copies within mitochondria, the mitochondrial DNA (mtDNA). mtDNA contains not only the genes encoding the thirteen protein part of the OXPHOS pathway, but also genes encoding 22 transfer RNA and 2 ribosomal RNA, essential for carrying out autonomous translation of the thirteen protein encoding genes in situ, i.e. within mitochondrion itself. This extremely complex genetic and biochemical machinery is essential for life, and mutations in mtDNA or in the very many (about 1500 presumably) proteins encoded in the nucleus and targeted to mitochondria, can produce a number of disabling conditions in infants, children and adults. In particular, mutation of mtDNA are strictly inherited through the maternal lineage of a family, because the egg is the only contributor of mitochondria to the zygote, whereas other mutations in nuclear genes follow the canonical mendelian rules of inheritance. We are actively committed to complete the long list of diseases due to OXPHOS dysfunction in humans, to explain the function of the new genes that are discovered at increasing pace in different patients with OXPHOS deficiency, and develop experimental therapies based on the use of drugs promoting mitochondrial homeostasis or by replacing the culprit genes using recombinant vectors.
In the past we have discovered a huge number of disease mutations in mtDNA and in nuclear genes functionally related to OXPHOS. This has provided not only some clues to treat patients, but also essential information to understand the complex biology underlying OXPHOS in humans. We are now opening a new frontier inner research by assaying and developing suitable drugs to improve OXPHOS efficiency in patients, and try the use of recombinant of harmless viral vectors (AAV) to convey to target tissue therapeutic genes. This work is currently performed in experimental animal, particularly recombinant mice, with the ultimate goal to transfer the most promising results to the cure of mitochondria patients.
The therapeutic project are ongoing in collaboration with my former group at the mitochondrial `Biology` Unit of the University of Cambridge, while ATB the same time I intend to create a center of excellence for high throughput, precision medicine to study patients, particularly children, with mitochondrial disease from the clinical, biochemical and genetic standpoints.
Because of the extreme complexity of mitochondrial biochemistry, genetics and pathophysiology, mitochondrial disease can strike people at any age, with any symptom and clinical course, affect virtually any organ either alone or in combination, and be transmitted according to either Mendelian or maternal inheritance, or even be occurring sporadically.
The genetic and biochemical intricacy of mitochondrial bioenergetics explains the extreme heterogeneity of mitochondrial disorders, a formidable challenge for both diagnostic workup and treatment. Therapeutic intervention is in fact hampered by incomplete elucidation of events leading to homeostatic default, cell degeneration and organ failure, underpinning the major clinical phenotypes associated with mitochondrial diseases. On the other hand, in spite of the formidable challenge given by the complexity of mitochondrial genetics, MRC biochemistry, and OXPHOS-associated homeostatic and execution pathways, most of mitochondrial disorders behave as recessive or, for mtDNA mutations, recessive-like, traits. This notion suggests that even partial correction of the genetic or biochemical defect may be sufficient to warrant significant amelioration of the phenotype in critical organs, and of the clinical outcome in affected individuals.
The wealth of knowledge gained during two decades of research in mitochondrial medicine make the effective treatment of a substantial fraction of mitochondrial disorders a difficult, challenging, but realistic goal. This achievement will constitute a major breakthrough in translational research and health care of rare diseases.
Our mission will build on these foundations with the ambitious aim of (i) elucidating the pathophysiology of prototypical mitochondrial disease conditions; and (ii) providing effective treatments for mitochondrial genetic diseases. Since results obtained from manipulation of cultured cells are often not transferable to whole organisms, we will focus on a set of specific defects of OXPHOS-related nuclear genes introduced in recombinant animal models that correspond to well-defined clinical conditions characterized by faulty OXPHOS in humans.
We are engaged in the organization of center of excellence for the biochemical and genetic diagnosis of mitochondrial disease patients and family, which will cooperate with the clinical structures available at the University of Padova to (i) offer an advanced tool for the clinical management of mitochondrial disorders in children and adults; (ii) discover new disease genes that may contribute to the complete characterization of mitochondrial disorders in humans and therefore (iii) elucidate several still unclear pathophysiological features of mitochondrial biology in mammalian organisms, that can contribute to the pathology of mitochondrial disease and pave the way for the development of rational and effective therapeutic approaches.
We have been developing and maintaining in our Unit the largest cohort in Europe of recombinant mouse lines carrying gene defects that correspond to specific human mitochondrial syndromes. The in vivo profiles concerning mitochondrial bioenergetics, homeostasis, and biogenesis have been characterized in most of these models and will be completed for the remaining ones in the next future. This set of mouse lines will be immediately exploited for the evaluation of new treatments. The extreme heterogeneity of mitochondrial disorders, due to the huge number of genes associated with specific conditions; the wide spectrum of symptoms and organs involved; and the complexity of the pathogenic mechanisms, all represent major obstacles for the development of rational therapies. Etiological correction of each and every disease entity is an unrealistic and in fact unfeasible approach. Contrariwise, we do need to devise therapeutic strategies with a concrete chance to be applied to a broad number of different conditions sharing faulty OXPHOS as the common biochemical hallmark. In parallel, we propose to obtain proof-of-principle evidence that specific mitochondrial disease conditions, dominated by single-organ involvement or accumulation of clearable toxic substances, can be corrected by relatively simple and realistically feasible approaches in vivo, mainly through gene therapy approaches. One of the major hurdles for an effective genetic cure of mitochondrial disease is the presence of the blood brain barrier, which protects the nerve cells but at the same time impedes the targeting of many drugs or therapeutic agents. We are committed to develop and test new adeno-associated viral vectors able to cross the BBB and convey to critical brain areas the therapeutic gene in amount and conditions adequate to its expression at therapeutically effective levels.
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MASSIMO ZEVIANI
- Group Leader, Veneto Institute for Molecular Medicine (VIMM), Padua (2019)
- Professor of Neurology, University of Padova, Italy (2019)
- Professor of Mitochondrial Medicine, University of Cambridge, and Director of the MRC Mitochondrial Biology Unit, Cambridge, UK (2013-2019)
- Director of the Department of Molecular Medicine at the Istituto Neurologico “Carlo Besta”, Milan, Italy (2011-2013)
Selected Awards
- ERC MitCare: Mitochondrial Medicine: developing treatments of OxPhos-defects in recombinant mammalian models (2013-2018)
CURRENT FUNDING
- Telethon-IT GGP19007: Experimental gene therapy in mitochondrial disorders (2019)
- Centres of Excellence in Neurodegeneration Mito-ND, Mitochondrial Neurodegeneration (2016-2018)
- Fondazione Renato Comini Onlus MitoFight: Experimental strategies to combat Pearson’s syndrome (2017-2022)
- ERC MitCare: Mitochondrial Medicine: developing treatments of OxPhos-defects in recombinant mammalian models (2013-2018)
- Fondazione Mariani, Establishing a Center for Mitochondrial Disorders of Infancy and Childhood (Individual grant) (2009-2013)
- Telethon-IT, Combating mitochondrial disorders (2011-2013)
- E-Rare, Mitochondrial Disorders – Connecting biobanks, empowering diagnostics and exploring disease models (Partner) (2012-2014)
- Fondazione CARIPLO Definition and characterization of disease genes in mitochondrial disorders (Coordinator) (2012-2013)
- Telethon-IT Identification and Characterization of Nuclear Genes Responsible for Human Mitochondrial Disorders (Coordinator) (2012-2014)