Metabolic implications of organelle–mitochondria communication

Gordaliza-Alaguero, Isabel; Cantó, Carlos; Zorzano, António

doi:10.15252/embr.201947928

Cited by 105 publications

(95 citation statements)

References 262 publications

(451 reference statements)

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“…The importance of Mfn2 is exemplified by Chen et al, who showed that cardiac-specific ablation of Mfn2 decreased ER-mitochondrial tethering by 30%, leading to a decreased mitochondrial Ca 2+ uptake, which hampers the response to physiological stress [40]. Besides Mfn2, several other proteins, including VAPB, PTPIP51, GRP75, VDAC1, BAP31, FIS1, and Pdzd8, are important for the tethering and interactions, such as Ca 2+ exchange, lipid trafficking, apoptosis, autophagy, and mitochondrial fission and fusion, between the ER and mitochondria [41]. Another example to stress the importance of the structural and physiological interactions between the ER and mitochondria consists of stromal interaction molecule 1 (STIM1).…”

Section: Interactions Between the Er And Mitochondriamentioning

confidence: 99%

Imbalance of ER and Mitochondria Interactions: Prelude to Cardiac Ageing and Disease?

Jin

Zhang

Brundel

et al. 2019

Cells

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Cardiac disease is still the leading cause of morbidity and mortality worldwide, despite some exciting and innovative improvements in clinical management. In particular, atrial fibrillation (AF) and heart failure show a steep increase in incidence and healthcare costs due to the ageing population. Although research revealed novel insights in pathways driving cardiac disease, the exact underlying mechanisms have not been uncovered so far. Emerging evidence indicates that derailed proteostasis (i.e., the homeostasis of protein expression, function and clearance) is a central component driving cardiac disease. Within proteostasis derailment, key roles for endoplasmic reticulum (ER) and mitochondrial stress have been uncovered. Here, we describe the concept of ER and mitochondrial stress and the role of interactions between the ER and mitochondria, discuss how imbalance in the interactions fuels cardiac ageing and cardiac disease (including AF), and finally assess the potential of drugs directed at conserving the interaction as an innovative therapeutic target to improve cardiac function. of 15including the ubiquitin-proteasomal system (UPS) and autophagy [9]. In general, cellular stress, including stress caused by cardiac disease, activates multiple stress pathways, including the cytosolic heat shock response, the endoplasmic reticulum (ER) unfolded protein response (UPR ER ), and the mitochondrial UPR (UPR mt ) [10][11][12].Within the PQC, the ER and mitochondria play a critical role in the regulation of protein homeostasis and the maintenance of normal cellular function. The ER is an essential organelle involved in protein synthesis, folding, and trafficking. As protein folding is an error-prone process, the PQC system of the ER is specialized in optimizing this process, thereby preserving cardiac protein quality and homeostasis [13]. As approximately 30% of the cardiomyocyte volume is comprised of mitochondria, the maintenance of a healthy and functional mitochondrial PQC system, which includes molecular chaperones (e.g., HSP60 and HSP10) and proteases (e.g., ClpP), is critical to conserve the energy balance and cardiomyocyte function. The PQC system in mitochondria activates, upon stress, protein folding assistance mechanisms and promotes clearance of misfolded proteins to preserve mitochondrial function [14,15].Thus, a healthy proteostasis in cardiomyocytes safeguards the proper contractile function in the heart. The ER and mitochondria are essential organelles for regulating protein homeostasis, thereby guaranteeing cardiomyocyte function and survival. Therefore, a deeper understanding of ER and mitochondrial function during health and cardiac disease is required to ultimately develop novel therapeutic strategies. Role of the ER in Cardiac HealthThe ER is an essential organelle supporting multiple cellular processes such as protein synthesis, protein folding, regulation of Ca 2+ homeostasis, and contribution to the generation of autophagosomes and peroxisomes [16]. The ER lumen constitutes of a specialized fol...

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Section: Interactions Between the Er And Mitochondriamentioning

confidence: 99%

Imbalance of ER and Mitochondria Interactions: Prelude to Cardiac Ageing and Disease?

Jin

Zhang

Brundel

et al. 2019

Cells

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“…The ATP produced through metabolic pathways is necessary to fuel the myriad of biological processes that take place within a cell to support its growth and viability. Metabolic bioenergetic signaling pathways are closely integrated with organelle-based processes, which together focus on balancing anabolic and catabolic cellular activities ( Thelen and Zoncu, 2017 ; Todkar et al, 2017 ; Gordaliza-Alaguero et al, 2019 ; Xia et al, 2019 ). Respectively, anabolism and catabolism function to drive the production versus degradation of biomass, which is necessary to balance cell and tissue growth, homeostasis, and survival.…”

Section: Metabolic Organelle Network Regulate Stem Cell Fatementioning

confidence: 99%

“…While many bioenergetic pathways exist that contribute to ATP production, a cell can be classified based on its relative reliance on two over-arching processes: oxidative phosphorylation (OxPhos) and glycolysis. These processes drive differential rates of ATP production and a unique complement of metabolite by-products ( Folmes et al, 2012 ; Zhang et al, 2018 ; Gordaliza-Alaguero et al, 2019 ; Intlekofer and Finley, 2019 ). Oxidative phosphorylation is linked to the mitochondrial electron transport chain (ETC) and fueled by energy precursors generated through the tricarboxylic acid cycle (TCA).…”

Section: Metabolic Organelle Network Regulate Stem Cell Fatementioning

confidence: 99%

“…A tethering complex that mediates mitochondrial–lysosome MCSs has been identified in yeast, where it is an important regulator of cell growth and is activated and maintained in response to metabolic activity ( Hönscher et al, 2014 ). Alterations in the abundance of organelle MCSs are observed in cases of aberrant metabolic regulation and metabolic disorders, and gene knockout studies of proteins that comprise MCSs have begun to reveal that the integrity of at least some of these contacts is indeed crucial to proper metabolic regulation ( Sebastián et al, 2012 , 2016 ; Gordaliza-Alaguero et al, 2019 ).…”

Section: Metabolic Organelle Network Regulate Stem Cell Fatementioning

confidence: 99%

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Organelle Cooperation in Stem Cell Fate: Lysosomes as Emerging Regulators of Cell Identity

Julian

Stanford

2020

Front. Cell Dev. Biol.

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Regulation of stem cell fate is best understood at the level of gene and protein regulatory networks, though it is now clear that multiple cellular organelles also have critical impacts. A growing appreciation for the functional interconnectedness of organelles suggests that an orchestration of integrated biological networks functions to drive stem cell fate decisions and regulate metabolism. Metabolic signaling itself has emerged as an integral regulator of cell fate including the determination of identity, activation state, survival, and differentiation potential of many developmental, adult, disease, and cancer-associated stem cell populations and their progeny. As the primary adenosine triphosphate-generating organelles, mitochondria are well-known regulators of stem cell fate decisions, yet it is now becoming apparent that additional organelles such as the lysosome are important players in mediating these dynamic decisions. In this review, we will focus on the emerging role of organelles, in particular lysosomes, in the reprogramming of both metabolic networks and stem cell fate decisions, especially those that impact the determination of cell identity. We will discuss the inter-organelle interactions, cell signaling pathways, and transcriptional regulatory mechanisms with which lysosomes engage and how these activities impact metabolic signaling. We will further review recent data that position lysosomes as critical regulators of cell identity determination programs and discuss the known or putative biological mechanisms. Finally, we will briefly highlight the potential impact of elucidating mechanisms by which lysosomes regulate stem cell identity on our understanding of disease pathogenesis, as well as the development of refined regenerative medicine, biomarker, and therapeutic strategies.

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“…In addition to their roles related to ATP production and cell death, mitochondria act as important cell hubs regulating calcium signaling, supplying intermediates for lipid synthesis, and modulating the production and removal of oxidants such as superoxide radical anions. Concomitantly, they sense nutrient availability and cooperate with metabolism-regulating pathways, including responses to insulin and its downstream effectors (del Campo et al, 2014;Cheng et al, 2010;Gordaliza-Alaguero et al, 2019;Wai and Langer, 2016;Zorzano et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Increased glycolysis is an early outcome of palmitate-mediated lipotoxicity

Kakimoto

Zorzano

Kowaltowski

2020

Preprint

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Palmitic acid is the most abundant saturated fatty acid in human serum. In cell culture systems, palmitate overload is considered a toxic stimulus, and promotes lipid accumulation, insulin resistance, endoplasmic reticulum stress, oxidative stress, as well as cell death. An increased supply of fatty acids has also been shown to change the predominant form of the mitochondrial network, although the metabolic effects of this change are still unclear. Here, we aimed to uncover the early bioenergetic outcomes of lipotoxicity. We incubated hepatic PLC/PRF/5 cells with palmitate conjugated to BSA and followed real-time oxygen consumption and extracellular acidification for 6 hours. Palmitate increased glycolysis as soon as 1 hour after the stimulus, while oxygen consumption was not disturbed, despite overt mitochondrial fragmentation and cellular reductive imbalance.Palmitate only induced mitochondrial fragmentation if glucose and glutamine were available, while glycolytic enhancement did not require glutamine, showing it is not dependent on morphological changes. NAD(P)H levels were significantly abrogated in palmitate-treated cells. Knockdown of the mitochondrial NAD(P) transhydrogenase or addition of the mitochondrial oxidant-generator menadione in control cells modulated ATP production from glycolysis. Indeed, using selective inhibitors, we found that the production of superoxide/hydrogen peroxide at the IQ site of electron transport chain complex I is associated with the metabolic rewiring promoted by palmitate, while not changing mitochondrial oxygen consumption. In conclusion, we demonstrate that increased glycolytic flux linked to mitochondrially-generated redox imbalance is an early bioenergetic result of palmitate overload and lipotoxicity.

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Metabolic implications of organelle–mitochondria communication

Cited by 105 publications

References 262 publications

Imbalance of ER and Mitochondria Interactions: Prelude to Cardiac Ageing and Disease?

Imbalance of ER and Mitochondria Interactions: Prelude to Cardiac Ageing and Disease?

Organelle Cooperation in Stem Cell Fate: Lysosomes as Emerging Regulators of Cell Identity

Increased glycolysis is an early outcome of palmitate-mediated lipotoxicity

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