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.
- 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)
- 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)