New Study Is Published Detailing Pathogenic Mechanisms Underlying Mitochondrial Encephalomyopathies

A team led by Antoni Barrientos, Ph.D., professor in the Department of Neurology and the Department of Biochemistry and Molecular Biology at the University of Miami Miller School of Medicine, has uncovered fundamental mechanisms underlying the biogenesis of the mitochondrial electron transport chain (ETC) enzymes. Findings of the study were recently published in the journal Nature Communications.

The research was supported by grants from the National Institutes of Health and the Muscular Dystrophy Association. Eva Nývltová, Ph.D., an associate scientist in the Barrientos lab supported by a fellowship from the American Heart Association, was the first author of the study, which was conducted with the collaboration of Oleh Khalimonchuk, Ph.D., professor of biochemistry at the University of Nebraska, Lincoln.

Mitochondria play functions critical for cell survival and death. Most prominently, they convert the energy in nutrients into chemical energy that is used to fuel cellular work. Dysfunctional mitochondria can cause devastating diseases, frequently with childhood onset, but the pathogenic mechanisms underlying these diseases remain to be fully understood.

The researchers have focused on the terminal ETC enzyme, known as cytochrome c oxidase or complex IV. During cellular respiration, oxygen binds to the catalytic center of cytochrome c oxidase, which contains heme a and copper, and is reduced to water. Defects in cytochrome c oxidase are among the most frequent cause of mitochondrial disorders. Among them, inefficient incorporation of the metal groups heme a and copper lead to severe cardio- and encephalopathies.

The paper, titled “Coordination of metal center biogenesis in human cytochrome c oxidase,” clarifies key aspects of how the metals are incorporated into the cytochrome c oxidase enzyme and what metallochaperones are involved. The findings provide clues to understanding the pathogenic mechanisms underlying these diseases and identifying new targets for therapeutic intervention.

“In this paper, we have discovered several regulatory mechanisms that are in place to regulate the coordinated incorporation of copper and heme into human cytochrome c oxidase,” said Dr. Barrientos. “The regulatory mechanisms are fundamental for cytochrome c oxidase assembly and function, and prevent the accumulation of heme-containing cytochrome c oxidase assembly intermediates lacking copper, which induce oxidative stress-mediated cytotoxicity.”

A Complex Process

The Barrientos lab has been working for 20 years to understand how the mitochondrial cytochrome c oxidase enzyme is assembled. The process is complicated by the fact that cytochrome c oxidase is formed by 14 protein subunits — three of which form the catalytic center of the enzyme and are encoded in the mitochondrial genome, and the rest of which are encoded in the nuclear genome.

Assembling all these proteins to form the full enzyme is arduous. Over the years, the Barrientos laboratory has contributed to identifying protein chaperones that help with the process, from inserting the metal groups in the catalytic core to bringing the more than 35 proteins together to form the complex.

“This study has been a tour de force because of the many proteins involved, but the data allow us now to understand better the pathology underlying mitochondrial cardiomyopathies and encephalomyopathies associated with cytochrome c oxidase deficiency,” Dr. Nývltová said.

The study revolves around a protein called COX11, which binds copper ions and delivers them to cytochrome c oxidase subunit 1 (COX1). Several other proteins, such as COX19 and the cardiomyopathy protein PET191, regulate this process. In addition, these proteins cooperate with metallochaperones that deliver heme A to COX1 or copper to subunit 2 (COX2), such as the cardiomyopathy and encephalomyopathy proteins SCO1, SCO2, COA6, COX10, or COX15.

Understanding Genetically Different Disorders

“The mechanisms that we are describing allow us not only to understand a single disease, but to connect pathogenic mechanisms across multiple genetically heterogeneous mitochondrial disorders,” Dr. Barrientos said. “Furthermore, we have identified new candidates for screening when looking for the genetic cause of mitochondrial diseases associated with cytochrome c oxidase deficiency.

“Our studies have mostly focused on the processes that regulate the incorporation of copper into the cytochrome c oxidase. We will now continue by investigating the mechanisms regulating heme insertion into the protein COX1, a process affected in cytochrome c oxidase-associated disorders,” he said. “Additionally, the present study has allowed us to identify a novel set of proteins, potentially relevant for mitochondrial respiration in health and disease, that we plan to characterize.”

Tags: American Heart Association, Dr. Antoni Barrientos, Dr. Eva Nyvltova, Miller School of Medicine, mitochondrial diseases, Muscular Dystrophy Association, National Institutes of Health, Nature Communications