Dr. Antonio Barrientos is a VA Research Health Science Specialist funded by a VA merit award, and a voting member of the Research and Development committee at the Miami VA since 2016. Dr. Barrientos is also a tenured Professor of Neurology and Biochemistry and Molecular Biology at the University of Miami Miller School of Medicine. The Barrientos laboratory focuses on unraveling the intricate mechanisms that govern the biogenesis of mitochondrial protein complexes and their interplay with the protein homeostatic machinery in various states—be it health, disease, or aging. Dr. Barrientos’ VA program addresses metabolic and mitochondrial alterations that are hallmarks of aging and neurodegeneration. One of the major challenges for the U.S. Department of Veterans Affairs is to extend the health-span of the veterans and their families as their physical and/or cognitive performance capabilities decline with age. Human neurodegenerative protein misfolding disorders, or proteinopathies, are associated with abnormal protein depositions in brain neurons. They include polyglutamine (polyQ) disorders such as Huntington’s disease and α-synucleinopathies such as Parkinson’s disease. Disclosing the basic molecular and metabolic alterations that occur during aging of post-mitotic cells, such as neurons, under proteotoxic stress is crucial for understanding the etiology of neuro-proteinopathies. The Barrientos’ program studies the mechanisms underlying neuroprotection by enhancement of mitochondrial biogenesis and overexpression of a new class of chaperones, the multifunctional NAD+ biosynthetic enzymes that act as molecular chaperones under stress. This program will reveal crucial relationships between metabolism and neurodegeneration and may lead to novel therapeutic approaches to modulate these neuroprotective pathways to counteract cellular toxicities and extend health-span. In addition to the VA, Dr. Barrientos' research activities receive support from various sources, including the NIG (NGMS Institute), the Muscular Dystrophy Association (MDA), and the Florida Department of Health (FDoH). The NIGMS award consolidates three classical RO1 awards and funds fundamental and translational studies on mitochondrial biogenesis to unravel how the mitochondrial gene expression system works from genome replication to transcription and translation, and the consequences of its failure. The MDA supports an innovative study on the role of aberrant mitochondrial RNA structures in mitochondrial diseases, while the FDoH award funds studies on novel mitochondrial protein synthesis inhibitors targeting leukemic cells in blood malignancy models. These non-VA studies provide approaches and fundamental knowledge regarding mitochondrial function that informs the projects under the VA program. Since 2018, he has published 6 book chapters, 7 review articles, and 29 research articles published in high-profile journals (e.g., Science, Nature Genet., Cell Metab., Nature Comm., Dev. Cell, Cell Reports, Nucleic Acids Res., eLife, Genome Biology, or the EMBO Journal). The number of articles and the quality of these journals indicate a consistent and ongoing record of productivity and accomplishments that have contributed to advance our field. Dr. Barrientos participates in active mentoring of the next generations of scientists. During his 20 years as an academic faculty, he has trained 12 postdoctoral associates and fellows, mentored 15 PhD students (3 currently), been on the dissertation committee of 26 graduate students, and was a mentor of 7 master’s students and 12 undergraduate students. Understanding the mechanisms underlying mitochondrial biogenesis in standard conditions and under stress is a grand challenge from both biological and biomedical perspectives. Dr. Barrientos’ program is anticipated to continue contributing significantly to bridging the knowledge gap in mitochondrial biogenesis in health and disease.

Neurodegenerative diseases involve protein buildup in neurons, leading to cell death. Searching for suppressors of proteotoxicity, we identified mitochondrial energy metabolism and the NAD+ biosynthetic salvage pathway as excellent targets. The goal of this program is to test the unconventional hypothesis that four NAD+ biosynthetic enzymes possess additional functions as cytoprotective chaperones in the context of proteotoxic stress in human neurons. We believe the proposed studies are germane to the important mission of the VA. Understanding the fundamental mechanisms that offer protection against proteotoxicity is crucial for comprehending the etiology of age-related neurodegenerative diseases prevalent in Veterans and their families and a prerequisite to devising therapeutic interventions aiming at neuroprotection, the ultimate goal of our program.