Antoni Barrientos

Antoni Barrientos
University of Miami Miller School of Medicine | UM · Departments of Neurology and Biochemistry

PhD

About

166
Publications
35,291
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Introduction
My research focus is on the biogenesis of the oxidative phosphorylation (OXPHOS) complexes and the mitochondrial protein synthesis apparatus in health, disease and aging. Check our website at Barrientoslab.org
Additional affiliations
May 2003 - present
University of Miami Miller School of Medicine
Position
  • Professor (Full)
Description
  • Website: Barrientoslab.org
May 2003 - January 2019
University of Miami Miller School of Medicine
Position
  • Professor (Full)

Publications

Publications (166)
Article
Full-text available
Background Oxidative phosphorylation (OXPHOS) complexes consist of nuclear and mitochondrial DNA-encoded subunits. Their biogenesis requires cross-compartment gene regulation to mitigate the accumulation of disproportionate subunits. To determine how human cells coordinate mitochondrial and nuclear gene expression processes, we tailored ribosome pr...
Article
Full-text available
Mitochondrial cytochrome c oxidase (CcO) or respiratory chain complex IV is a heme aa3-copper oxygen reductase containing metal centers essential for holo-complex biogenesis and enzymatic function that are assembled by subunit-specific metallochaperones. The enzyme has two copper sites located in the catalytic core subunits. The COX1 subunit harbor...
Article
Targeted signaling inhibitors for hematologic malignancies may lead to limited clinical efficacy due to the outgrowth of subpopulations with alternative pathways independent of the drug target. Recent studies have shown that some forms of hematologic malignancies (Ashton et al., 2018) and solid tumors (Molina et al., 2018) have an energy metabolism...
Article
Full-text available
In Saccharomyces cerevisiae, mitoribosomes are composed of a 54S large subunit (mtLSU) and a 37S small subunit (mtSSU). The two subunits altogether contain 73 mitoribosome proteins (MRPs) and two ribosomal RNAs (rRNAs). Although mitoribosomes preserve some similarities with their bacterial counterparts, they have significantly diverged by acquiring...
Article
The response to oxygen availability is a fundamental process concerning metabolism and survival/death in all mitochondria-containing eukaryotes. However, the known oxygen-sensing mechanism in mammalian cells depends on pVHL, which is only found among metazoans but not in other species. Here, we present an alternative oxygen-sensing pathway regulate...
Article
Full-text available
The ATPase Family AAA Domain Containing 3A (ATAD3A), is a mitochondrial inner membrane protein conserved in metazoans. ATAD3A has been associated with several mitochondrial functions, including nucleoid organization, cholesterol metabolism, and mitochondrial translation. To address its primary role, we generated a neuronal-specific conditional knoc...
Article
Targeted signaling inhibitors for hematologic malignancies may lead to limited clinical efficacy due to the outgrowth of subpopulations with alternative pathways independent of the drug target. Relapse/refractory disease that results from treatment with targeted signaling inhibitors is a major hurdle in obtaining curative responses. Interestingly,...
Preprint
Full-text available
The carotid body (CB) is the major chemoreceptor for blood oxygen in the control of ventilation in mammals, contributing to physiological adaptation to high altitude, pregnancy, and exercise, and its hyperactivity is linked to chronic conditions such as sleep-disorder breathing, hypertension, chronic heart failure, airway constriction, and metaboli...
Preprint
Full-text available
Oxidative phosphorylation (OXPHOS) complexes consist of nuclear and mitochondrial DNA- encoded subunits. Their biogenesis requires cross-compartment gene regulation to mitigate the accumulation of disproportionate subunits. To determine how human cells coordinate mitochondrial and nuclear gene expression processes, we established an optimized ribos...
Article
Full-text available
Human neurodegenerative proteinopathies are disorders associated with abnormal protein depositions in brain neurons. They include polyglutamine (polyQ) conditions such as Huntington’s disease (HD) and α-synucleinopathies such as Parkinson’s disease (PD). Overexpression of NMNAT/Nma1, an enzyme in the NAD+ biosynthetic salvage pathway, acts as an ef...
Article
Mitochondrial ribosomes (mitoribosomes) are tethered to the mitochondrial inner membrane to facilitate the cotranslational membrane insertion of the synthesized proteins. We report cryo–electron microscopy structures of human mitoribosomes with nascent polypeptide, bound to the insertase oxidase assembly 1–like (OXA1L) through three distinct contac...
Article
Mitoribosomes catalyze essential protein synthesis within mitochondria. Mitoribosome biogenesis is assisted by an increasing number of assembly factors, among which guanosine triphosphate hydrolases (GTPases) are the most abundant class. Here, we review recent progress in our understanding of mitoribosome assembly GTPases. We describe their shared...
Article
Full-text available
Arginyltransferase 1 (ATE1) is an evolutionary-conserved eukaryotic protein that localizes to the cytosol and nucleus. It is the only known enzyme in metazoans and fungi that catalyzes posttranslational arginylation. Lack of arginylation has been linked to an array of human disorders, including cancer, by altering the response to stress and the reg...
Article
Full-text available
Mitochondria control life and death in eukaryotic cells. Harboring a unique circular genome, a by-product of an ancient endosymbiotic event, mitochondria maintains a specialized and evolutionary divergent protein synthesis machinery, the mitoribosome. Mitoribosome biogenesis depends on elements encoded in both the mitochondrial genome (the RNA comp...
Chapter
Full-text available
Mitochondria contain ribosomes (mitoribosomes) specialized in the synthesis of a handful of proteins essential for oxidative phosphorylation. Therefore, mitoribosome integrity and function are essential for the life of eukaryotic cells and lesions that affect them result in devastating human disorders. To broadly analyze the integrity and assembly...
Article
Full-text available
The biogenesis and function of eukaryotic cytochrome c oxidase or mitochondrial respiratory chain complex IV (CIV) undergo several levels of regulation to adapt to changing environmental conditions. Adaptation to hypoxia and oxidative stress involves CIV subunit isoform switch, changes in phosphorylation status, and modulation of CIV assembly and e...
Preprint
Human neurodegenerative proteinopathies are disorders associated with abnormal protein depositions in brain neurons. They include polyglutamine (polyQ) conditions such as Huntington’s disease (HD) and α-synucleinopathies such as Parkinson’s disease (PD). Overexpression of NMNAT/Nma1, an enzyme in the NAD ⁺ biosynthetic salvage pathway, acts as a po...
Article
Full-text available
Respiratory chains are crucial for cellular energy conversion and consist of multi-subunit complexes that can assemble into super-complexes. These structures have been intensively characterized in various organisms, but their physiological roles remain unclear. Here, we elucidate their function by leveraging a high-resolution structural model of ye...
Article
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By using negatively charged Coomassie brilliant blue G-250 dye to induce a charge shift on proteins, blue native polyacrylamide gel electrophoresis (BN-PAGE) allows resolution of enzymatically active multiprotein complexes extracted from cellular or subcellular lysates while retaining their native conformation. BN-PAGE was first developed to analyz...
Article
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GTPBP5 (MTG2) manuscript: supplemental material
Article
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Biogenesis of mammalian mitochondrial ribosomes (mitoribosomes) involves several conserved small GTPases. Here, we report that the Obg family protein GTPBP5 or MTG2 is a mitochondrial protein whose absence in a TALEN-induced HEK293T knockout (KO) cell line leads to severely decreased levels of the 55S monosome and attenuated mitochon-drial protein...
Article
Mitochondrial respiratory chain complexes I, III, and IV can associate into larger structures termed supercomplexes or respirasomes, thereby generating structural interdependences among the individual complexes yet to be understood. In patients, nonsense mutations in complex IV subunit genes cause severe encephalomyopathies randomly associated with...
Article
Full-text available
Mitochondria are the major consumer of oxygen in eukaryotic cells, owing to the requirement of oxygen to generate ATP through the mitochondrial respiratory chain (MRC) and the oxidative phosphorylation system (OXPHOS). This aerobic energy transduction is more efficient than anaerobic processes such as glycolysis. Hypoxia, a condition in which envir...
Article
Full-text available
The mitochondrial respiratory chain enzymes are organized as individual complexes and supercomplexes, whose biogenesis remains to be fully understood. To disclose the role of the human Hypoxia Inducible Gene Domain family proteins HIGD1A and HIGD2A in these processes, we generate and characterize HIGD-knockout (KO) cell lines. We show that HIGD2A c...
Chapter
The maintenance and expression of the mammalian mitochondrial genome (mtDNA) is a fundamental aspect of mitochondrial biogenesis. The mtDNA is transcribed as precursor polycistronic transcripts containing 11 mRNAs, 2 rRNAs, punctuated by 22 tRNAs. They require to be processed to engage in the assembly of unique mitochondrial ribosomes (the rRNAs),...
Data
Supplementary data corresponding to a paper published in Nucleic Acids Research, where we describe the role of the mitoribosomal protein mS38 in mitoribosome assembly and function.
Article
Full-text available
Message-specific translational regulation mechanisms shape the biogenesis of multimeric oxida-tive phosphorylation (OXPHOS) enzyme in mito-chondria from the yeast Saccharomyces cerevisiae. These mechanisms, driven mainly by the action of mRNA-specific translational activators, help to coordinate synthesis of OXPHOS catalytic subunits by the mitorib...
Article
Full-text available
The mitochondrial respiratory chain is organized in a dynamic set of supercomplexes (SCs). The COX7A2L protein is essential for mammalian SC III2+IV assembly. However, its function in respirasome (SCs I+III2+IVn) biogenesis remains controversial. To unambiguously determine the COX7A2L role, we generated COX7A2L-knockout (COX7A2L-KO) HEK293T and U87...
Article
Full-text available
Most steps on the biogenesis of the mitochondrial ribosome (mitoribosome) occur near the mitochon-drial DNA nucleoid, in RNA granules, which contain dedicated RNA metabolism and mitoribosome assembly factors. Here, analysis of the RNA granule proteome identified the presence of a set of small GT-Pases that belong to conserved families of ribosome a...
Article
Full-text available
Over the last few decades, the budding yeast Saccharomyces cerevisiae has been extensively used as a valuable organism to explore mechanisms of aging and human age-associated neurodegenerative disorders. Yeast models can be used to study loss of function of disease-related conserved genes and to investigate gain of function activities, frequently p...
Article
Full-text available
Mammalian mitochondrial ribosomes (mitoribosomes) synthesize 13 proteins, essential components of the oxidative phosphorylation system. They are linked to mitochondrial disorders, often involving cardiomyopathy. Mitoribosome biogenesis is assisted by multiple cofactors whose specific functions remain largely uncharacterized. Here, we examined the r...
Article
Mitoribosomes are specialized for the synthesis of hydrophobic membrane proteins encoded by mtDNA, all essential for oxidative phosphorylation. Despite their linkage to human mitochondrial diseases and the recent cryoelectron microscopy reconstruction of yeast and mammalian mitoribosomes, how they are assembled remains obscure. Here, we dissected t...
Article
Full-text available
Elucidating the biology of yeast in its full complexity has major implications for science, medicine and industry. One of the most critical processes determining yeast life and physiology is cellular demise. However, the investigation of yeast cell death is a relatively young field, and a widely accepted set of concepts and terms is still missing....
Article
Full-text available
Elucidating the biology of yeast in its full complexity has major implications for science, medicine and industry. One of the most critical processes determining yeast life and physiology is cellular demise. However, the investigation of yeast cell death is a relatively young field, and a widely accepted set of concepts and terms is still missing....
Article
Full-text available
Saccharomyces cerevisiae mitoribosomes are specialized in the translation of a few number of highly hydrophobic membrane proteins, components of the oxidative phosphorylation system. Mitochondrial characteristics, such as the membrane system and its redox state driven mitoribosomes evolution through great diversion from their bacterial and cytosoli...
Article
Full-text available
Mutations in coiled-coil-helix-coiled-coil-helix-domain containing 10 (CHCHD10), a mitochondrial twin CX9C protein whose function is still unknown, cause myopathy, motor neuron disease, frontotemporal dementia, and Parkinson's disease. Here, we investigate CHCHD10 topology and its protein interactome, as well as the effects of CHCHD10 depletion or...
Article
Mitochondrial cytochrome c oxidase (COX) is the primary site of cellular oxygen consumption and is essential for aerobic energy generation in the form of ATP. Human COX is a copper-heme A hetero-multimeric complex formed by 3 catalytic core subunits encoded in the mitochondrial DNA and 11 subunits encoded in the nuclear genome. Investigations over...
Article
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Members of the DEAD-box family are often multifunctional proteins involved in several RNA transactions. Among them, yeast Saccharomyces cerevisiae Mss116 participates in mitochondrial intron splicing and, under cold stress, also in mitochondrial transcription elongation. Here, we show that Mss116 interacts with the mitoribosome assembly factor Mrh4...
Article
Mitochondria play fundamental roles in the regulation of life and death of eukaryotic cells. They mediate aerobic energy conversion through the oxidative phosphorylation (OXPHOS) system, and harbor and control the intrinsic pathway of apoptosis. As a descendant of a bacterial endosymbiont, mitochondria retain a vestige of their original genome (mtD...
Article
Full-text available
Defects in mitochondrial cytochrome c oxidase or respiratory chain complex IV (CIV) assembly are a frequent cause of human mitochondrial disorders. Specifically, mutations in four conserved assembly factors impinging the biogenesis of the mitochondrion-encoded catalytic core subunit 2 (COX2) result in myopathies. These factors afford stability of n...
Article
Full-text available
Defects in mitochondrial respiratory chain complex IV (CIV) frequently cause encephalocardiomyopathies. Human CIV assembly involves 14 subunits of dual genetic origin and multiple nucleus‐encoded ancillary factors. Biogenesis of the mitochondrion‐encoded copper/heme‐containing COX1 subunit initiates the CIV assembly process. Here, we show that the...
Article
Full-text available
Arginyltransferase 1 (Ate1) mediates protein arginylation, a poorly understood protein posttranslational modification (PTM) in eukaryotic cells. Previous evidence suggest a potential involvement of arginylation in stress response and this PTM was traditionally considered anti-apoptotic based on the studies of individual substrates. However, here we...
Article
Full-text available
Defects in mitochondrial biogenesis and function are common in many neurodegenerative disorders, including Huntington’s disease (HD). We have previously shown that in yeast models of HD, enhancement of mitochondrial biogenesis through overexpression of Hap4, the catalytic subunit of the transcriptional complex that regulates mitochondrial gene expr...
Article
Full-text available
A network of conserved proteases known as the intramitochondrial quality control (IMQC) system is central to mitochondrial protein homeostasis and cellular health. IMQC proteases also appear to participate in establishment of signaling cues for mitochondria-to-nucleus communication. However, little is known about this process. Here we show that in...
Article
Full-text available
Aim: Mitochondrial cytochrome c oxidase (COX), the last enzyme of the respiratory chain, catalyzes the reduction of oxygen to water and therefore is essential for cell function and viability. COX is a multimeric complex, whose biogenesis is extensively regulated. One type of control targets Cox1, a key COX enzymatic core subunit translated on mito...
Article
Full-text available
To gain a wider view of the pathways that regulate mitochondrial function, we combined the effect of heat stress on respiratory capacity with the discovery potential of a genome-wide screen in Saccharomyces cerevisiae. We identified 105 new genes whose deletion impairs respiratory growth at 37°C by interfering with processes such as transcriptional...
Article
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Dominant optic atrophy (DOA) and axonal peripheral neuropathy (Charcot-Marie-Tooth type 2, or CMT2) are hereditary neurodegenerative disorders most commonly caused by mutations in the canonical mitochondrial fusion genes OPA1 and MFN2, respectively. In yeast, homologs of OPA1 (Mgm1) and MFN2 (Fzo1) work in concert with Ugo1, for which no human equi...
Article
Full-text available
A redox-regulated import pathway consisting of Mia40 and Erv1 mediates the import of cysteine-rich proteins into the mitochondrial intermembrane space. Mia40 is the oxidoreductase that inserts two disulfide bonds into the substrate simultaneously. However, Mia40 has one redox-active cysteine pair, resulting in ambiguity about how Mia40 accepts nume...