Antoni Barrientos, professor of neurology and of biochemistry and molecular biology at the University of Miami Miller School of Medicine in Miami, Fla., was awarded an MDA research grant totaling $300,000 over a period of three years to address a knowledge gap about mitochondrial protein complex assembly defects, which are a frequent cause of inherited mitochondrial myopathies. This project will not only improve our understanding of a process fundamentally central to mitochondrial processing, but also explore interventions that improve functioning and disease phenotypes.
Please describe your current research.
Defects in mitochondrial cytochrome c oxidase (COX) assembly are a frequent cause of mitochondrial encephalomyopathies in humans. This enzyme, formed by multiple proteins, is necessary for cellular respiration and for cellular energy production. COX performs its functions thanks to metal groups, copper and heme, that are incorporated into two of its protein components. Copper delivery and insertion require specific chaperone proteins, COX11 and SCO1/2, that receive copper from a protein called COX17. Several additional proteins of the COX17 family exist in mitochondria, and their roles remain unknown.
The main objective of this project is to gain insight into the role of two of these COX17 family proteins, originally identified by our group: CMC1 and CMC2. Using innovative human cultured cell models, cell lines from patients, and new gene editing technology, we aim to better understand the normal function of these proteins, and how COX assembly is impacted when these protein are absent or abnormal. These proteins may be targets when screening for mutations responsible for mitochondrial encephalomyopathies associated with COX deficiencies.
What inspired you to study mitochondrial myopathies?
I have devoted my entire career to mitochondrial research. During my Ph.D. studies in Barcelona (Spain, 1996) my work focused on the biochemical screening of muscle biopsies of patients with suspicion of mitochondrial diseases, and further identification of the specific mitochondrial respiratory chain defect at the biochemical and molecular levels. I was tremendously intrigued by the biology and pathophysiology of these organelles, since they control cellular life and death.
I then developed postdoctoral studies at the University of Miami (FL) and at Columbia University (NY) to gain expertise on mechanistic studies using yeast and human cell culture models of mitochondrial disorders and in 2003 started my own program at the University of Miami on mitochondrial biogenesis in health, neuromuscular disease and aging.
What is your area of focus within the mitochondrial myopathy field and why is it important?
My main research interest focuses on the biogenesis of mitochondrial membrane protein complexes in health, neuromuscular disease and aging. I am most specifically interested in the mitochondrial translation machinery and in the components of the mitochondrial respiratory chain and oxidative phosphorylation system, involved in biological energy transduction. Our aims are to understand pathogenic mechanisms underlying mitochondrial encephalomyopathies and to identify targets for therapeutic interventions.
The study of mitochondria is now a very “hot issue” for both basic and clinical research. Mitochondria are not only the “energy factories” of the cell but they also house a multiplicity of pathways that serve to regulate cellular life and death. Importantly, mitochondria are involved in prevalent human diseases of wide social impact, most notably neurodegenerative disorders, but also in cancer and the aging process. In addition, alterations in mitochondrial production of energy are the cause of fatal childhood diseases such as neuromyopathies and cardiomyopathies. Despite more than 50 years of work on the topic, a full understanding of mitochondrial biogenesis at the molecular level has not yet been achieved.
Why is it important that MDA continue to fund research in mitochondrial myopathies?
Mitochondrial diseases are still considered “rare” diseases, given their clinical and biochemical heterogeneity. However, they affect 1:5,000 individuals as a whole and currently there is no cure for mitochondrial disorders. Only continuous basic and translational investigations in the field will allow devising effective therapeutic interventions.
What do you feel people impacted by mitochondrial myopathies can have the most hope about with respect to research right now?
Over the last few years, serious advances in gene editing have allowed the development of “gene therapy” interventions for mitochondrial diseases due to mutations in the mitochondrial DNA, which are being tested in animal models. In general, most mitochondrial syndromes are today better understood thanks to basic research efforts.
Does your work have any potential implications for other disease fields?
The project funded by MDA impacts all mitochondrial encephalomyopathies and cardiomyopathies associated with mitochondrial cytochrome c oxidase alterations, including the most well-known Leigh’s syndrome.
To learn more about how MDA research is accelerating treatments and cures for mitochondrial myopathy, please visit mda.org.