Mitochondria are cellular power plants, and are especially important in neurons, muscle and other tissues that use a lot of energy. Still, many aspects of these critical organelles are poorly understood, including how the large protein complexes assemble into super complexes that produce energy packets in the chemical form of adenosine triphosphate, or ATP.
“This is fundamental for cellular metabolism because these enzymes produce energy for all our cells,” said Antonio Barrientos, Ph.D., professor in the departments of Neurology and Biochemistry and Molecular Biology at the University of Miami Miller School of Medicine.
Alba Timón-Gómez, Ph.D., a postdoctoral fellow in the Barrientos lab, added, “These enzyme complexes are formed by multiple proteins, but little is known about how they are put together.”
But now, in an article published in the journal Cell Reports, Dr. Barrientos, Dr. Timón-Gómez, who was first author on the paper, and colleagues have illuminated the roles two proteins — HIGD1A and HIGD2A — play in assembling mitochondrial protein complexes. These findings clarify how the absence of these proteins can disrupt mitochondrial function and could help identify potential therapeutic and diagnostic targets.
The Barrientos lab has been working to decipher the biogenesis of these protein complexes for several years, both to understand the basic biology and illuminate human mitochondrial diseases, such as hyperthopic cardiomyopathy and encephalomyopathy, and fatal heart or brain conditions, respectively, that afflict newborns.
“This is highly relevant for patients because sometimes they might have a gene mutation that affects only one of the proteins from one of the respiratory complexes” said Dr. Barrientos, who was the paper’s senior author. “However, that single mutation can generate functional defects in multiple enzymes because they form super complexes.”
To better understand how these mitochondrial protein complexes are assembled, the group generated cells that completely lack HIGD1A and HIGD2A, adding in the proteins under different environmental conditions (e.g., changing oxygen levels) to observe how the cells behaved. Their investigation showed both proteins play both separate and overlapping roles in putting together the mitochondrial protein complexes and super complexes.
Perhaps most significantly, the researchers found mitochondria can choose from several pathways when building these complexes. This flexibility may help them respond rapidly to different environmental stresses and respond to energy demands.
One potential stressor is hypoxia, or low oxygen levels. It has been well-established that some patients with mitochondrial defects do better when placed in hypoxic environments. While this is hardly practical for long-term treatment, the results from this study may offer a simpler way to provide therapeutic benefit.
“The problem is that, of course, it's difficult to maintain a person their whole life in a hypoxic chamber,” Dr. Timón-Gómez said. “So, if we are able to identify targets that can mimic this process, that would be a great finding.”
In addition to mitochondrial diseases, this work could have implications for cancer research. Because tumors grow so rapidly, and are often poorly vascularized, they tend towards hypoxia. Understanding how these protein complexes are assembled under hypoxic conditions could help researchers determine how tumors thrive in these low-oxygen environments.
In addition to offering potential therapeutic targets, this research could lead to new diagnostic tests for mitochondrial disorders. It could also help answer other questions about mitochondrial function, such as how they can shift food sources as needed.
“We are working on this untested hypothesis currently dominating the field that having some plasticity in the system, so the enzymes can either associate in these complex structures or dissociate as individual entities in different proportions, allow the mitochondria to metabolize different nutrients,” Dr. Barrientos said. “So, they are able to take electrons, or power, coming from fat or proteins differently, depending on how the enzymes are associated. I think that if this hypothesis is proven, it can reveal the functional significance of the mitochondrial respiratory chain super complex organization.”