bims-minimp 2022-05-22 papers

on Mitochondria, innate immunity, proteostasis

Issue of 2022–05–22
eight papers selected by
Hanna Salmonowicz, International Institute of Molecular Mechanisms and Machines of the Polish Academy of Sciences

Mitochondrial calcium uniporter stabilization preserves energetic homeostasis during Complex I impairment.
Beyond being an energy supplier, ATP synthase is a sculptor of mitochondrial cristae.
Mitochondrial complex complexification.
Revealing the Impact of Mitochondrial Fitness During Early Neural Development Using Human Brain Organoids.
Protein lifetimes in aged brains reveal a proteostatic adaptation linking physiological aging to neurodegeneration.
Upregulation of mitochondrial ATPase inhibitory factor 1 (ATPIF1) mediates increased glycolysis in mouse hearts.
Identification of a modulator of the actin cytoskeleton, mitochondria, nutrient metabolism and lifespan in yeast.
Inhibition of mitochondrial complex I reverses NOTCH1-driven metabolic reprogramming in T-cell acute lymphoblastic leukemia.

Nat Commun. 2022 May 19. 13(1): 2769

Mitochondrial calcium uniporter stabilization preserves energetic homeostasis during Complex I impairment.

Enrique Balderas, David R Eberhardt, Sandra Lee, John M Pleinis, Salah Sommakia, Anthony M Balynas, Xue Yin, Mitchell C Parker, Colin T Maguire, Scott Cho, Marta W Szulik, Anna Bakhtina, Ryan D Bia, Marisa W Friederich, Timothy M Locke, Johan L K Van Hove, Stavros G Drakos, Yasemin Sancak, Martin Tristani-Firouzi, Sarah Franklin, Aylin R Rodan, Dipayan Chaudhuri.

Calcium entering mitochondria potently stimulates ATP synthesis. Increases in calcium preserve energy synthesis in cardiomyopathies caused by mitochondrial dysfunction, and occur due to enhanced activity of the mitochondrial calcium uniporter channel. The signaling mechanism that mediates this compensatory increase remains unknown. Here, we find that increases in the uniporter are due to impairment in Complex I of the electron transport chain. In normal physiology, Complex I promotes uniporter degradation via an interaction with the uniporter pore-forming subunit, a process we term Complex I-induced protein turnover. When Complex I dysfunction ensues, contact with the uniporter is inhibited, preventing degradation, and leading to a build-up in functional channels. Preventing uniporter activity leads to early demise in Complex I-deficient animals. Conversely, enhancing uniporter stability rescues survival and function in Complex I deficiency. Taken together, our data identify a fundamental pathway producing compensatory increases in calcium influx during Complex I impairment.

DOI: https://doi.org/10.1038/s41467-022-30236-4
Biochim Biophys Acta Bioenerg. 2022 May 14. pii: S0005-2728(22)00038-X. [Epub ahead of print]1863(6): 148569

Beyond being an energy supplier, ATP synthase is a sculptor of mitochondrial cristae.

Héctor Miranda-Astudillo, Marcos Ostolga-Chavarría, Pierre Cardol, Diego González-Halphen.

  Mitochondrial F1FO-ATP synthase plays a key role in cellular bioenergetics; this enzyme is present in all eukaryotic linages except in amitochondriate organisms. Despite its ancestral origin, traceable to the alpha proteobacterial endosymbiotic event, the actual structural diversity of these complexes, due to large differences in their polypeptide composition, reflects an important evolutionary divergence between eukaryotic lineages. We discuss the effect of these structural differences on the oligomerization of the complex and the shape of mitochondrial cristae.

Keywords:  ATP synthase; F(1)-F(O) ATPase; Lineage-specific subunits; Mitochondrial ATPase

DOI:  https://doi.org/10.1016/j.bbabio.2022.148569
Science. 2022 May 20. 376(6595): 794-795

Mitochondrial complex complexification.

Martijn A Huynen, Dei M Elurbe.

Variation in complex composition provides clues about the function of individual subunits.

DOI: https://doi.org/10.1126/science.abq0368
Front Mol Neurosci. 2022 ;15 840265

Revealing the Impact of Mitochondrial Fitness During Early Neural Development Using Human Brain Organoids.

Alejandra I Romero-Morales, Vivian Gama.

  Mitochondrial homeostasis -including function, morphology, and inter-organelle communication- provides guidance to the intrinsic developmental programs of corticogenesis, while also being responsive to environmental and intercellular signals. Two- and three-dimensional platforms have become useful tools to interrogate the capacity of cells to generate neuronal and glia progeny in a background of metabolic dysregulation, but the mechanistic underpinnings underlying the role of mitochondria during human neurogenesis remain unexplored. Here we provide a concise overview of cortical development and the use of pluripotent stem cell models that have contributed to our understanding of mitochondrial and metabolic regulation of early human brain development. We finally discuss the effects of mitochondrial fitness dysregulation seen under stress conditions such as metabolic dysregulation, absence of developmental apoptosis, and hypoxia; and the avenues of research that can be explored with the use of brain organoids.

Keywords:  brain organoids; glycolysis; mitochondria; neural precursor cells; neural rosettes; oxidative phosphorylation; stem cells

DOI:  https://doi.org/10.3389/fnmol.2022.840265
Sci Adv. 2022 May 20. 8(20): eabn4437

Protein lifetimes in aged brains reveal a proteostatic adaptation linking physiological aging to neurodegeneration.

Verena Kluever, Belisa Russo, Sunit Mandad, Nisha Hemandhar Kumar, Mihai Alevra, Alessandro Ori, Silvio O Rizzoli, Henning Urlaub, Anja Schneider, Eugenio F Fornasiero.

Aging is a prominent risk factor for neurodegenerative disorders (NDDs); however, the molecular mechanisms rendering the aged brain particularly susceptible to neurodegeneration remain unclear. Here, we aim to determine the link between physiological aging and NDDs by exploring protein turnover using metabolic labeling and quantitative pulse-SILAC proteomics. By comparing protein lifetimes between physiologically aged and young adult mice, we found that in aged brains protein lifetimes are increased by ~20% and that aging affects distinct pathways linked to NDDs. Specifically, a set of neuroprotective proteins are longer-lived in aged brains, while some mitochondrial proteins linked to neurodegeneration are shorter-lived. Strikingly, we observed a previously unknown alteration in proteostasis that correlates to parsimonious turnover of proteins with high biosynthetic costs, revealing an overall metabolic adaptation that preludes neurodegeneration. Our findings suggest that future therapeutic paradigms, aimed at addressing these metabolic adaptations, might be able to delay NDD onset.

DOI: https://doi.org/10.1126/sciadv.abn4437
J Clin Invest. 2022 May 16. pii: e155333. [Epub ahead of print]132(10):

Upregulation of mitochondrial ATPase inhibitory factor 1 (ATPIF1) mediates increased glycolysis in mouse hearts.

Bo Zhou, Arianne Caudal, Xiaoting Tang, Juan D Chavez, Timothy S McMillen, Andrew Keller, Outi Villet, Mingyue Zhao, Yaxin Liu, Julia Ritterhoff, Pei Wang, Stephen C Kolwicz, Wang Wang, James E Bruce, Rong Tian.

  In hypertrophied and failing hearts, fuel metabolism is reprogrammed to increase glucose metabolism, especially glycolysis. This metabolic shift favors biosynthetic function at the expense of ATP production. Mechanisms responsible for the switch are poorly understood. We found that inhibitory factor 1 of the mitochondrial FoF1-ATP synthase (ATPIF1), a protein known to inhibit ATP hydrolysis by the reverse function of ATP synthase during ischemia, was significantly upregulated in pathological cardiac hypertrophy induced by pressure overload, myocardial infarction, or α-adrenergic stimulation. Chemical cross-linking mass spectrometry analysis of hearts hypertrophied by pressure overload suggested that increased expression of ATPIF1 promoted the formation of FoF1-ATP synthase nonproductive tetramer. Using ATPIF1 gain- and loss-of-function cell models, we demonstrated that stalled electron flow due to impaired ATP synthase activity triggered mitochondrial ROS generation, which stabilized HIF1α, leading to transcriptional activation of glycolysis. Cardiac-specific deletion of ATPIF1 in mice prevented the metabolic switch and protected against the pathological remodeling during chronic stress. These results uncover a function of ATPIF1 in nonischemic hearts, which gives FoF1-ATP synthase a critical role in metabolic rewiring during the pathological remodeling of the heart.

Keywords:  Cardiology; Heart failure; Metabolism; Mitochondria; Structural biology

DOI:  https://doi.org/10.1172/JCI155333
Nat Commun. 2022 May 16. 13(1): 2706

Identification of a modulator of the actin cytoskeleton, mitochondria, nutrient metabolism and lifespan in yeast.

Cierra N Sing, Enrique J Garcia, Thomas G Lipkin, Thomas M Huckaba, Catherine A Tsang, Arielle C Coughlin, Emily J Yang, Istvan R Boldogh, Ryo Higuchi-Sanabria, Liza A Pon.

In yeast, actin cables are F-actin bundles that are essential for cell division through their function as tracks for cargo movement from mother to daughter cell. Actin cables also affect yeast lifespan by promoting transport and inheritance of higher-functioning mitochondria to daughter cells. Here, we report that actin cable stability declines with age. Our genome-wide screen for genes that affect actin cable stability identified the open reading frame YKL075C. Deletion of YKL075C results in increases in actin cable stability and abundance, mitochondrial fitness, and replicative lifespan. Transcriptome analysis revealed a role for YKL075C in regulating branched-chain amino acid (BCAA) metabolism. Consistent with this, modulation of BCAA metabolism or decreasing leucine levels promotes actin cable stability and function in mitochondrial quality control. Our studies support a role for actin stability in yeast lifespan, and demonstrate that this process is controlled by BCAA and a previously uncharacterized ORF YKL075C, which we refer to as actin, aging and nutrient modulator protein 1 (AAN1).

DOI: https://doi.org/10.1038/s41467-022-30045-9
Nat Commun. 2022 May 19. 13(1): 2801

Inhibition of mitochondrial complex I reverses NOTCH1-driven metabolic reprogramming in T-cell acute lymphoblastic leukemia.

Natalia Baran, Alessia Lodi, Yogesh Dhungana, Shelley Herbrich, Meghan Collins, Shannon Sweeney, Renu Pandey, Anna Skwarska, Shraddha Patel, Mathieu Tremblay, Vinitha Mary Kuruvilla, Antonio Cavazos, Mecit Kaplan, Marc O Warmoes, Diogo Troggian Veiga, Ken Furudate, Shanti Rojas-Sutterin, Andre Haman, Yves Gareau, Anne Marinier, Helen Ma, Karine Harutyunyan, May Daher, Luciana Melo Garcia, Gheath Al-Atrash, Sujan Piya, Vivian Ruvolo, Wentao Yang, Sriram Saravanan Shanmugavelandy, Ningping Feng, Jason Gay, Di Du, Jun J Yang, Fieke W Hoff, Marcin Kaminski, Katarzyna Tomczak, R Eric Davis, Daniel Herranz, Adolfo Ferrando, Elias J Jabbour, M Emilia Di Francesco, David T Teachey, Terzah M Horton, Steven Kornblau, Katayoun Rezvani, Guy Sauvageau, Mihai Gagea, Michael Andreeff, Koichi Takahashi, Joseph R Marszalek, Philip L Lorenzi, Jiyang Yu, Stefano Tiziani, Trang Hoang, Marina Konopleva.

T-cell acute lymphoblastic leukemia (T-ALL) is commonly driven by activating mutations in NOTCH1 that facilitate glutamine oxidation. Here we identify oxidative phosphorylation (OxPhos) as a critical pathway for leukemia cell survival and demonstrate a direct relationship between NOTCH1, elevated OxPhos gene expression, and acquired chemoresistance in pre-leukemic and leukemic models. Disrupting OxPhos with IACS-010759, an inhibitor of mitochondrial complex I, causes potent growth inhibition through induction of metabolic shut-down and redox imbalance in NOTCH1-mutated and less so in NOTCH1-wt T-ALL cells. Mechanistically, inhibition of OxPhos induces a metabolic reprogramming into glutaminolysis. We show that pharmacological blockade of OxPhos combined with inducible knock-down of glutaminase, the key glutamine enzyme, confers synthetic lethality in mice harboring NOTCH1-mutated T-ALL. We leverage on this synthetic lethal interaction to demonstrate that IACS-010759 in combination with chemotherapy containing L-asparaginase, an enzyme that uncovers the glutamine dependency of leukemic cells, causes reduced glutaminolysis and profound tumor reduction in pre-clinical models of human T-ALL. In summary, this metabolic dependency of T-ALL on OxPhos provides a rational therapeutic target.

DOI: https://doi.org/10.1038/s41467-022-30396-3