bims-misrem 2020-11-01 papers

Issue of 2020‒11‒01
five papers selected by
Rafael Antonio Casuso Pérez
University of Granada

Front Physiol. 2020 ;11 554904

The Mitochondrial Ca2+ Uptake and the Fine-Tuning of Aerobic Metabolism.

Gaia Gherardi, Halenya Monticelli, Rosario Rizzuto, Cristina Mammucari.

Recently, the role of mitochondrial activity in high-energy demand organs and in the orchestration of whole-body metabolism has received renewed attention. In mitochondria, pyruvate oxidation, ensured by efficient mitochondrial pyruvate entry and matrix dehydrogenases activity, generates acetyl CoA that enters the TCA cycle. TCA cycle activity, in turn, provides reducing equivalents and electrons that feed the electron transport chain eventually producing ATP. Mitochondrial Ca2+ uptake plays an essential role in the control of aerobic metabolism. Mitochondrial Ca2+ accumulation stimulates aerobic metabolism by inducing the activity of three TCA cycle dehydrogenases. In detail, matrix Ca2+ indirectly modulates pyruvate dehydrogenase via pyruvate dehydrogenase phosphatase 1, and directly activates isocitrate and α-ketoglutarate dehydrogenases. Here, we will discuss the contribution of mitochondrial Ca2+ uptake to the metabolic homeostasis of organs involved in systemic metabolism, including liver, skeletal muscle, and adipose tissue. We will also tackle the role of mitochondrial Ca2+ uptake in the heart, a high-energy consuming organ whose function strictly depends on appropriate Ca2+ signaling.

Keywords: aerobic metabolism; mitochondria; mitochondrial calcium uniporter (MCU); mitochondrial calcium uptake; systemic metabolism

DOI: https://doi.org/10.3389/fphys.2020.554904

Aging Cell. 2020 Oct 31. e13265

Mastering organismal aging through the endoplasmic reticulum proteostasis network.

Rebecca C Taylor, Claudio Hetz.

The aging process is characterized by a progressive decline in the function of most tissues, representing the main risk factor in the development of a variety of human diseases. Studies in multiple animal models have demonstrated that interventions that improve the capacity to maintain endoplasmic reticulum (ER) proteostasis prolong life and healthspan. ER stress is monitored by the unfolded protein response (UPR), a signaling pathway that mediates adaptive processes to restore proteostasis or the elimination of damaged cells by apoptosis. Here, we discuss recent advances in understanding the significance of the UPR to aging and its implications for the maintenance of cell physiology of various cell types and organs. The possible benefits of targeting the UPR to extend healthspan and reduce the risk of developing age-related diseases are also discussed.

Keywords: ER stress; aging; autophagy; cell-nonautonomous; protein misfolding; proteostasis

DOI: https://doi.org/10.1111/acel.13265

Cell Physiol Biochem. 2020 Oct 30. 54(6): 1101-1114

Association Between L-OPA1 Cleavage and Cardiac Dysfunction During Ischemia-Reperfusion Injury in Rats.

Keishla M Rodríguez-Graciani, Xavier R Chapa-Dubocq, Lee Ann MacMillan-Crow, Sabzali Javadov.

BACKGROUND/AIMS: Structural and functional alterations in mitochondria, particularly, the inner mitochondrial membrane (IMM) plays a critical role in mitochondria-mediated cell death in response to cardiac ischemia-reperfusion (IR) injury. The integrity of IMM can be affected by two potential intra-mitochondrial factors: i) mitochondrial matrix swelling, and ii) proteolytic cleavage of the long optic atrophy type 1 (L-OPA1), an IMM-localized dynamin-like GTPase engaged in the regulation of structural organization and integrity of the mitochondrial cristae. However, the relationship between these two factors in response to oxidative stress remains unclear. Here, we elucidated the effects of cardiac IR injury on L-OPA1 cleavage and OMA1 activity.METHODS: Langendorff-mode perfused isolated rat hearts were subjected to 25-min of global ischemia followed by 90-min reperfusion in the presence or absence of XJB-5-131 (XJB, a mitochondria-targeting ROS scavenger) and sanglifehrin A (SfA, a permeability transition pore inhibitor).
RESULTS: XJB in combination with SfA increased post-ischemic recovery of cardiac function and reduced mitochondrial ROS production at 30- and 60-min reperfusion and affected mitochondrial swelling. L-OPA1 levels were reduced in IR hearts; however, neither XJB, SfA, and their combination prevented IR-induced reduction of L-OPA1 cleavage. Likewise, IR increased the OMA1 enzymatic activity, which remained unchanged in the presence of XJB and/or SfA.
CONCLUSION: IR-induced cardiac and mitochondrial dysfunctions are associated with OMA1 activation and L-OPA1 cleavage. However, XJB, SfA, and their combination do not prevent these changes despite improved heart and mitochondria function, thus, suggesting that different mechanisms can be implicated in L-OPA1 processing in response to cardiac IR injury.

Keywords: Cardiac ischemia-reperfusion; Mitochondria; Optic atrophy type 1 protein; Reactive oxygen species; Mitochondrial swelling; Permeability transition pores

DOI: https://doi.org/10.33594/000000303

Int J Mol Sci. 2020 Oct 22. pii: E7841. [Epub ahead of print]21(21):

Mitochondrial Function and Protein Turnover in the Diaphragm are Altered in LLC Tumor Model of Cancer Cachexia.

Megan E Rosa-Caldwell, Conner A Benson, David E Lee, Jacob L Brown, Tyrone A Washington, Nicholas P Greene, Michael P Wiggs.

It is established that cancer cachexia causes limb muscle atrophy and is strongly associated with morbidity and mortality; less is known about how the development of cachexia impacts the diaphragm. The purpose of this study was to investigate cellular signaling mechanisms related to mitochondrial function, reactive oxygen species (ROS) production, and protein synthesis during the development of cancer cachexia. C57BL/J6 mice developed Lewis Lung Carcinoma for either 0 weeks (Control), 1 week, 2 weeks, 3 weeks, or 4 weeks. At designated time points, diaphragms were harvested and analyzed. Mitochondrial respiratory control ratio was ~50% lower in experimental groups, which was significant by 2 weeks of cancer development, with no difference in mitochondrial content markers COXIV or VDAC. Compared to the controls, ROS was 4-fold elevated in 2-week animals but then was not different at later time points. Only one antioxidant protein, GPX3, was altered by cancer development (~70% lower in experimental groups). Protein synthesis, measured by a fractional synthesis rate, appeared to become progressively lower with the cancer duration, but the mean difference was not significant. The development and progression of cancer cachexia induces marked alterations to mitochondrial function and ROS production in the diaphragm and may contribute to increased cachexia-associated morbidity and mortality.

Keywords: FOXO; mTOR; mitochondrial function; muscle atrophy; oxidative stress; protein degradation; protein synthesis

DOI: https://doi.org/10.3390/ijms21217841

Nat Metab. 2020 Oct 26.

Mitochondrial pyruvate carriers are required for myocardial stress adaptation.

In addition to fatty acids, glucose and lactate are important myocardial substrates under physiologic and stress conditions. They are metabolized to pyruvate, which enters mitochondria via the mitochondrial pyruvate carrier (MPC) for citric acid cycle metabolism. In the present study, we show that MPC-mediated mitochondrial pyruvate utilization is essential for the partitioning of glucose-derived cytosolic metabolic intermediates, which modulate myocardial stress adaptation. Mice with cardiomyocyte-restricted deletion of subunit 1 of MPC (cMPC1-/-) developed age-dependent pathologic cardiac hypertrophy, transitioning to a dilated cardiomyopathy and premature death. Hypertrophied hearts accumulated lactate, pyruvate and glycogen, and displayed increased protein O-linked N-acetylglucosamine, which was prevented by increasing availability of non-glucose substrates in vivo by a ketogenic diet (KD) or a high-fat diet, which reversed the structural, metabolic and functional remodelling of non-stressed cMPC1-/- hearts. Although concurrent short-term KDs did not rescue cMPC1-/- hearts from rapid decompensation and early mortality after pressure overload, 3 weeks of a KD before transverse aortic constriction was sufficient to rescue this phenotype. Together, our results highlight the centrality of pyruvate metabolism to myocardial metabolism and function.

DOI: https://doi.org/10.1038/s42255-020-00288-1