Molecular Diagnosis and Coping Mechanisms in Mitochondrial Myopathies

Prof. Alexis Jourdain, University of Lausanne

Abstract (lay summary see below)

Mitochondrial myopathies are a heterogeneous group of neuromuscular diseases caused by defects
in mitochondria, an organelle crucially involved in cell metabolism and energy production. Mitochondrial
myopathies are generally hereditary and arise mainly through genetic lesions which affect muscle tissue
directly, or indirectly through effects on the central nervous system. Common symptoms include muscle
weakness, cramps, hypotonia and atrophy. The diversity of mitochondrial syndromes poses a major
challenge for the diagnosis of mitochondrial myopathies, and currently whole genome-sequencing has
failed to assign the disease-causing genes in about 50% of patients, hindering reliable molecular
diagnosis and tracking of familial transmission. Furthermore, our limited fundamental knowledge of
mitochondrial disorders has also had repercussions for therapy and to date, there are no successful
treatments for mitochondrial myopathies. In the present application, I propose to (1) exploit recently
developed genome perturbation technologies to understand the aberrant metabolism frequently
observed in cells with dysfunctional mitochondria and thereby to discover the genes responsible for
mitochondrial malfunction; and (2) study changes in the composition and activity of mitochondria in
the muscle lineage, during differentiation of both normal cells and cells carrying pathological
mitochondrial DNA mutations, to discover the natural coping mechanisms known to provide
resistance to mitochondrial dysfunction in differentiated muscle. The findings from these two parts
of the project will not only help in the molecular diagnosis of suspected mitochondrial myopathies and
allow tracking of familial transmission, but may also provide novel therapeutic strategies based on the
use of precision mitochondrial medicines.

Lay summary

Les myopathies mitochondriales sont un groupe hétérogène de maladie génétiques pour lesquelles
il n’existe aucun remède. Ces pathologies sont pourtant parmi les plus fréquentes dans le groupe des
maladies rares, et sont associées à des symptômes sévères, telles que la faiblesse musculaire,
l’atrophie et la paralysie. Une limitation majeure pour le traitement des myopathies mitochondriales
vient de leur diagnostique difficile à réaliser en raison de leur hétérogénéité, et de la connaissance
partielle que nous avons des mitochondries, souvent appelées « centrales énergétiques des cellules »,
dont les dysfonctionnements sont à la base de ces pathologies. Ce projet propose de découvrir les
gènes responsables des maladie mitochondriales, ainsi que les mécanismes qui permettent aux
cellules musculaires atteintes par ces maladies de survivre. Ces découvertes permettront d’améliorer
le diagnostique des maladies mitochondriales et pourront être exploitées à fin de traitement.