Mitochondrial function in physiology and neurological diseases

Marco Spinazzi, Hospital Practitioner

(Marco.Spinazzi @ chu-angers.fr)

Marco.Spinazzi @ chu-angers.fr (Marco.Spinazzi @ chu-angers.fr)

Keywords: mitochondrial diseases, neurodegeneration, mitochondrial biology, biomarkers, therapy

State of the art and objectives

Mitochondrial are essential cellular organelles that fulfil functions needed for cell survival, such as energy and heat production, regulation of cell death, and cell signalling. Not surprisingly muscles and neurons, that heavily rely on these activities, are the most susceptible organs to acquired and genetically determined mitochondrial diseases. Despite the impressive breakthrough of genetics which led to the identification of an exponentially growing number of mutations in gene encoding mitochondrial proteins, the understanding of the mechanisms underlying these severe diseases are still very limited, the diagnosis difficult, and therapeutical options still lacking. Our aim consists in identifying key pathogenetic mechanisms of mitochondrial diseases in cellular, animal, and material collected from patients by using unbiased omics approaches.

Main results from the last 5 years

• Identification of a crucial role of the inner mitochondrial membrane protein protease PARL in the nervous system, involved in the pathobiology of Parkinson Disease and diabetes, and proving solid arguments to solve several long-lasting controversies in the field
• Definition of protocols for all round functional analysis of mitochondrial function from different cells, organs, species (human, mouse, flies, yeast).
• Providing the first study on the biochemical mechanisms of a rare treatable human condition due to severe copper deficiency, causing a dramatic form of spinal cord and nerve degeneration
• Providing critical contribution to the role of the long-non-coding RNA SAMMSON in the mitochondrial homeostasis of melanoma
• Continous commitment to translational research projects involving mitochondria in diseases

Main publications and patents from the 5 last years

• Spinazzi M, Radaelli E, Horré K, Arranz AM, Gounko NV, Agostinis P, Maia TM, Impens F, Morais VA, Lopez-Lluch G, Serneels L, Navas P, De Strooper B. Parl Deficiency In Mouse Causes Complex III Defects, Coenzyme Q depletion, and Leigh-Like Syndrome. Proc Natl Acad Sci U S A. 2019;116:277-286.
• Borgia D, Malena A, Spinazzi M, Desbats MA, Salviati L, Russell AP, Miotto G, Tosatto L, Pegoraro E, Sorarù G, Pennuto M, Vergani L. Increased mitophagy in the skeletal muscle of spinal and bulbar muscular atrophy Human Molecular Genetics 2017; 26:1087-1103. Spinazzi M et De Strooper B. PARL: the mitochondrial rhomboid. Seminars Developmental Cell Biology. 2016; 60:19-28.
• Leucci E, Vendramin R, Spinazzi M, Laurette P, Fiers M, Wouters J, Radaelli E, Eyckerman S, Leonelli C, Vanderheyden K, Rogiers A, Hermans E, Baatsen P, Aerts S, Amant F, Van Aelst S, van den Oord J, de Strooper B, Davidson I, Lafontaine DL, Gevaert K, Vandesompele J, Mestdagh P, Marine JC. Melanoma addiction to the long noncoding RNA SAMMSON. Nature. 2016; 531:518-22.
• Mancuso M, Orsucci D, Angelini C, Bertini E, Carelli V, Comi GP, Federico A, Minetti C, Moggio M, Mongini T, Tonin P, Toscano A, Bruno C, Ienco EC, Filosto M, Lamperti C, Diodato D, Moroni I, Musumeci O, Pegoraro E, Spinazzi M, Ahmed N, Sciacco M, Vercelli L, Ardissone A, Zeviani M, Siciliano G.”Mitochondrial neuropathies”: A survey from the large cohort of the Italian Neuromuscul Disord 2016; 26:272-6.
• Desbats MA, Vetro A, Limongelli I, Lunardi G, Casarin A, Doimo M, Spinazzi M, Angelini C, Cenacchi G, Burlina A, Rodriguez Hernandez MA, Chiandetti L, Clementi M, Trevisson E, Navas P, Zuffardi O, Salviati L.Primary coenzyme Q10 deficiency presenting as fatal neonatal multiorgan failure. Eur J Hum Genet. 2015; 23:1254-8.
• Papadopoulou AS, Serneels L, Achsel T, Mandemakers W, Callaerts-Vegh Z, Dooley J, Lau P, Ayoubi T, Radaelli E, Spinazzi M, Neumann M, Hébert SS, Silahtaroglu A, Liston A, D'Hooge R, Glatzel M, De Strooper B. Deficiency of the miR-29a/b-1 cluster leads to ataxic features and cerebellar alterations in mice. Neurobiol Dis. 2014; 73C:275-288.
• Spinazzi M, Sghirlanzoni A, Salviati L, Angelini C. Impaired copper and iron metabolism in blood cells and muscles of patients affected by copper deficiency myeloneuropathy. Neuropathology Applied Neurobiology. 2014; 40:888-98.

Collaborations

• Prof. Bart De Strooper, Laboratory for the research on Neurodegenerative Diseases, KU Leuven, Belgium
• Prof. Enrico Radaelli, University of Pennsylvania School of Veterinary Medicine, USA
• Prof. Francis Impens, Proteomic Expertise Center, VIB-UGent Center for Medical Biotechnology, Gent, Belgium
• Prof. Placido Navas and Guillermo Lopez Lluch, University of Sevilla, Spain
• Prof. Ilka Wittig Frankfurt Macromolecular Complexes Goethe-Universität Frankfurt, Germany

Acknowledgements for the financial supports

• European Molecular Biology Organisation (ALTF 648)