Organelle transporters and inter-organelle communication as drivers of metabolic regulation and cellular homeostasis

Jain, Aakriti; Zoncu, Roberto

doi:10.1016/j.molmet.2022.101481

Cited by 46 publications

(23 citation statements)

References 173 publications

(191 reference statements)

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“…In this study we have assumed that the metabolic enzymes belong to either mitochondrial or cytosolic compartments, and thus do not move between these compartments. However, it is known that the metabolites themselves can move between compartments, with the help of transport proteins [ 6 ]. For mitochondria the solute carrier family 25 (SLC25) is important, and with 53 members it is the largest family of solute transporters in humans [ 35 ].…”

Section: Discussionmentioning

confidence: 99%

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FunHoP analysis reveals upregulation of mitochondrial genes in prostate cancer

Rise

Tessem²,

Drabløs³

et al. 2022

PLoS ONE

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Mitochondrial activity in cancer cells has been central to cancer research since Otto Warburg first published his thesis on the topic in 1956. Although Warburg proposed that oxidative phosphorylation in the tricarboxylic acid (TCA) cycle was perturbed in cancer, later research has shown that oxidative phosphorylation is activated in most cancers, including prostate cancer (PCa). However, more detailed knowledge on mitochondrial metabolism and metabolic pathways in cancers is still lacking. In this study we expand our previously developed method for analyzing functional homologous proteins (FunHoP), which can provide a more detailed view of metabolic pathways. FunHoP uses results from differential expression analysis of RNA-Seq data to improve pathway analysis. By adding information on subcellular localization based on experimental data and computational predictions we can use FunHoP to differentiate between mitochondrial and non-mitochondrial processes in cancerous and normal prostate cell lines. Our results show that mitochondrial pathways are upregulated in PCa and that splitting metabolic pathways into mitochondrial and non-mitochondrial counterparts using FunHoP adds to the interpretation of the metabolic properties of PCa cells.

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Section: Discussionmentioning

confidence: 99%

“…There are several reasons why cellular processes are divided between different compartments in the cell [ 6 ]. Individual subcellular compartments may define different microenvironments, favoring optimal activity for important enzymes, for example with respect to pH or ions, like zinc ions as mentioned above.…”

Section: Introductionmentioning

confidence: 99%

FunHoP analysis reveals upregulation of mitochondrial genes in prostate cancer

Rise

Tessem²,

Drabløs³

et al. 2022

PLoS ONE

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show abstract

“…MCS are specialized small areas of close apposition between two organelles and at the LE/Lys-ER interface, lipid and cholesterol transfer proteins, together with tethers, sorting nexins, membrane channels, SNAREs, small Rab-GTPases and annexins mediate ion and lipid exchange [9][10][11][12]145,146]. It would go beyond the scope of this review to list all MCS-associated proteins, and we recommend excellent reviews that address the association of MCS with cancer-related events for further reading [147][148][149][150]. Most important here, NPC1-dependent and -independent cholesterol transfer mechanisms across MCS between LE/Lys and the ER involve members of the StARD and ORP families, Rab7 and their regulators and effectors, as well as the scaffolding protein annexin AnxA6 [9][10][11][12]145,146], all of which with links to cancer that will be described in more detail in the following sections.…”

Section: Potential Roles Of Le/lys-chol Transfer Across Membrane Cont...mentioning

confidence: 99%

Linking Late Endosomal Cholesterol with Cancer Progression and Anticancer Drug Resistance

Nguyen

Jose

Wahba

et al. 2022

IJMS

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Cancer cells undergo drastic metabolic adaptions to cover increased bioenergetic needs, contributing to resistance to therapies. This includes a higher demand for cholesterol, which often coincides with elevated cholesterol uptake from low-density lipoproteins (LDL) and overexpression of the LDL receptor in many cancers. This implies the need for cancer cells to accommodate an increased delivery of LDL along the endocytic pathway to late endosomes/lysosomes (LE/Lys), providing a rapid and effective distribution of LDL-derived cholesterol from LE/Lys to other organelles for cholesterol to foster cancer growth and spread. LDL-cholesterol exported from LE/Lys is facilitated by Niemann–Pick Type C1/2 (NPC1/2) proteins, members of the steroidogenic acute regulatory-related lipid transfer domain (StARD) and oxysterol-binding protein (OSBP) families. In addition, lysosomal membrane proteins, small Rab GTPases as well as scaffolding proteins, including annexin A6 (AnxA6), contribute to regulating cholesterol egress from LE/Lys. Here, we summarize current knowledge that links upregulated activity and expression of cholesterol transporters and related proteins in LE/Lys with cancer growth, progression and treatment outcomes. Several mechanisms on how cellular distribution of LDL-derived cholesterol from LE/Lys influences cancer cell behavior are reviewed, some of those providing opportunities for treatment strategies to reduce cancer progression and anticancer drug resistance.

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“…A compartmentalized architecture requires cells to connect metabolic modules between organelles [ 9 ], and many of the emerging links between organelle communication and the aging process arise from these metabolic connections. Pioneering work in yeast models revealed that mitochondrial declines during aging are at least partly the result of failures in another distal organelle, the vacuole/lysosome [ 47 ].…”

Section: Transfer Of Ions and Polar Metabolitesmentioning

confidence: 99%

Fundamental roles for inter-organelle communication in aging

Donahue

Ruark

Burkewitz

2022

Biochemical Society Transactions

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Advances in public health have nearly doubled life expectancy over the last century, but this demographic shift has also changed the landscape of human illness. Today, chronic and age-dependent diseases dominate the leading causes of morbidity and mortality worldwide. Targeting the underlying molecular, genetic and cell biological drivers of the aging process itself appears to be an increasingly viable strategy for developing therapeutics against these diseases of aging. Towards this end, one of the most exciting developments in cell biology over the last decade is the explosion of research into organelle contact sites and related mechanisms of inter-organelle communication. Identification of the molecular mediators of inter-organelle tethering and signaling is now allowing the field to investigate the consequences of aberrant organelle interactions, which frequently seem to correlate with age-onset pathophysiology. This review introduces the major cellular roles for inter-organelle interactions, including the regulation of organelle morphology, the transfer of ions, lipids and other metabolites, and the formation of hubs for nutrient and stress signaling. We explore how these interactions are disrupted in aging and present findings that modulation of inter-organelle communication is a promising avenue for promoting longevity. Through this review, we propose that the maintenance of inter-organelle interactions is a pillar of healthy aging. Learning how to target the cellular mechanisms for sensing and controlling inter-organelle communication is a key next hurdle for geroscience.

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Organelle transporters and inter-organelle communication as drivers of metabolic regulation and cellular homeostasis

Cited by 46 publications

References 173 publications

FunHoP analysis reveals upregulation of mitochondrial genes in prostate cancer

FunHoP analysis reveals upregulation of mitochondrial genes in prostate cancer

Linking Late Endosomal Cholesterol with Cancer Progression and Anticancer Drug Resistance

Fundamental roles for inter-organelle communication in aging

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