RESUMO

Cancer is a leading cause of death worldwide. All major tumor suppressors and oncogenes are now recognized to have fundamental connections with metabolic pathways. A hallmark feature of cancer cells is a reprogramming of their metabolism even when nutrients are available. Increasing evidence indicates that most cancer cells rely on mitochondrial metabolism to sustain their energetic and biosynthetic demands. Mitochondria are functionally and physically coupled to the endoplasmic reticulum (ER), the major calcium (Ca2+) storage organelle in mammalian cells, through special domains known as mitochondria-ER contact sites (MERCS). In this domain, the release of Ca2+ from the ER is mainly regulated by inositol 1,4,5-trisphosphate (IP3) receptors (IP3Rs), a family of Ca2+ release channels activated by the ligand IP3. IP3R mediated Ca2+ release is transferred to mitochondria through the mitochondrial Ca2+ uniporter (MCU). Once in the mitochondrial matrix, Ca2+ activates several proteins that stimulate mitochondrial performance. The role of IP3R and MCU in cancer, as well as the other proteins that enable the Ca2+ communication between these two organelles is just beginning to be understood. Here, we describe the function of the main players of the ER mitochondrial Ca2+ communication and discuss how this particular signal may contribute to the rise and development of cancer traits.

Assuntos

RESUMO

Cellular senescence generates a permanent cell cycle arrest, characterized by apoptosis resistance and a pro-inflammatory senescence-associated secretory phenotype (SASP). Physiologically, senescent cells promote tissue remodeling during development and after injury. However, when accumulated over a certain threshold as happens during aging or after cellular stress, senescent cells contribute to the functional decline of tissues, participating in the generation of several diseases. Cellular senescence is accompanied by increased mitochondrial metabolism. How mitochondrial function is regulated and what role it plays in senescent cell homeostasis is poorly understood. Mitochondria are functionally and physically coupled to the endoplasmic reticulum (ER), the major calcium (Ca2+) storage organelle in mammalian cells, through special domains known as mitochondria-ER contacts (MERCs). In this domain, the release of Ca2+ from the ER is mainly regulated by inositol 1,4,5-trisphosphate receptors (IP3Rs), a family of three Ca2+ release channels activated by a ligand (IP3). IP3R-mediated Ca2+ release is transferred to mitochondria through the mitochondrial Ca2+ uniporter (MCU), where it modulates the activity of several enzymes and transporters impacting its bioenergetic and biosynthetic function. Here, we review the possible connection between ER to mitochondria Ca2+ transfer and senescence. Understanding the pathways that contribute to senescence is essential to reveal new therapeutic targets that allow either delaying senescent cell accumulation or reduce senescent cell burden to alleviate multiple diseases.

Assuntos

RESUMO

In the last few years, metabolism has been shown to be controlled by cross-organelle communication. The relationship between the endoplasmic reticulum and mitochondria/lysosomes is the most studied; here, inositol 1,4,5-triphosphate (IP3) receptor (IP3R)-mediated calcium (Ca2+) release plays a central role. Recent evidence suggests that IP3R isoforms participate in synthesis and degradation pathways. This minireview will summarize the current findings in this area, emphasizing the critical role of Ca2+ communication on organelle function as well as catabolism and anabolism, particularly in cancer.

RESUMO

The inositol 1,4,5-triphosphate receptor (InsP3R)-mediated calcium (Ca2+) transfer to mitochondria is important to maintain mitochondrial respiration and bioenergetics in normal and cancer cells, even though cancer cells have defective oxidative phosphorylation (OXPHOS). Here, we discuss how tumor mitochondria could become a feasible therapeutic target to treat tumors that depend on reductive carboxylation.

RESUMO

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy whose chemoresistance and relapse persist as a problem despite significant advances in its chemotherapeutic treatments. Mitochondrial metabolism has emerged as an interesting therapeutic target given its essential role in maintaining bioenergetic and metabolic homeostasis. T-ALL cells are characterized by high levels of mitochondrial respiration, making them suitable for this type of intervention. Mitochondrial function is sustained by a constitutive transfer of calcium from the endoplasmic reticulum to mitochondria through the inositol 1,4,5-trisphosphate receptor (InsP3R), making T-ALL cells vulnerable to its inhibition. Here, we determine the bioenergetic profile of the T-ALL cell lines CCRF-CEM and Jurkat and evaluate their sensitivity to InsP3R inhibition with the specific inhibitor, Xestospongin B (XeB). Our results show that T-ALL cell lines exhibit higher mitochondrial respiration than non-malignant cells, which is blunted by the inhibition of the InsP3R. Prolonged treatment with XeB causes T-ALL cell death without affecting the normal counterpart. Moreover, the combination of XeB and glucocorticoids significantly enhanced cell death in the CCRF-CEM cells. The inhibition of InsP3R with XeB rises as a potential therapeutic alternative for the treatment of T-ALL.

Assuntos

RESUMO

Cytosolic calcium (cCa2+) entry into mitochondria is facilitated by the mitochondrial membrane potential (ΔΨm), an electrochemical gradient generated by the electron transport chain (ETC). Is has been assumed that as long as mutations that affect the ETC do not affect the ΔΨm, the mitochondrial Ca2+ (mCa2+) homeostasis remains normal. We show that knockdown of NDUFAF3 and SDHB reduce ETC activity altering mCa2+ efflux and influx rates while ΔΨm remains intact. Shifting the equilibrium toward lower [Ca2+]m accumulation renders cells resistant to death. Our findings reveal an unexpected relationship between complex I and II with the mCa2+ homeostasis independent of ΔΨm.

Assuntos

RESUMO

The interruption of endoplasmic reticulum (ER)-mitochondrial Ca2+ communication induces a bioenergetic crisis characterized by an increase of MTOR-independent AMPK-dependent macroautophagic/autophagic flux, which is not sufficient to reestablish the metabolic and energetic homeostasis in cancer cells. Here, we propose that upon ER-mitochondrial Ca2+ transfer inhibition, AMPK present at the mitochondria-associated membranes (MAMs) activate localized autophagy via BECN1 (beclin 1). This local response could prevent the proper interorganelle communication that would allow the autophagy-derived metabolites to reach the necessary anabolic pathways to maintain mitochondrial function and cellular homeostasis. Abbreviations: 3MA: 3-methyladenine; ADP: adenosine diphosphate; AMP: adenosine monophosphate; ATG13: autophagy related 13; ATG14: autophagy related 14; ATP: adenosine triphosphate; BECN1: beclin 1; Ca2+: calcium; DNA: deoxyribonucleic acid; ER: endoplasmic reticulum; GEF: guanine nucleotide exchange factor; ITPR: inositol 1,4,5-trisphosphate receptor; MAMs: mitochondria-associated membranes; MCU: mitochondrial calcium uniporter; MTOR: mechanistic target of rapamycin kinase; MTORC1: MTOR complex 1; OCR: oxygen consumption rate; PtdIns3K: class III phosphatidylinositol 3-kinase; RB1CC1/FIP200: RB1 inducible coiled-coil 1; RPTOR: regulatory associated protein of MTOR complex 1; RYRs: ryanodine receptors; STK11/LKB1: serine/threonine kinase 11; TCA: tricarboxylic acid; TSC2: TSC complex subunit 2; ULK1: unc-51 like autophagy activating kinase 1; V-ATPase: vacuolar-type H+-ATPase; VDAC: voltage dependent anion channel; XeB: xestospongin B.

Assuntos

RESUMO

Cancer is characterized by an uncontrolled cell proliferation rate even under low nutrient availability, which is sustained by a metabolic reprograming now recognized as a hallmark of cancer. Warburg was the first to establish the relationship between cancer and mitochondria; however, he interpreted enhanced aerobic glycolysis as mitochondrial dysfunction. Today it is accepted that many cancer cell types need fully functional mitochondria to maintain their homeostasis. Calcium (Ca2+)-a key regulator of several cellular processes-has proven to be essential for mitochondrial metabolism. Inositol 1,4,5-trisphosphate receptor (IP3R)-mediated Ca2+ transfer from the endoplasmic reticulum to the mitochondria through the mitochondrial calcium uniporter (MCU) proves to be essential for the maintenance of mitochondrial function and cellular energy balance. Both IP3R and MCU are overexpressed in several cancer cell types, and the inhibition of the Ca2+ communication between these two organelles causes proliferation arrest, migration decrease, and cell death through mechanisms that are not fully understood. In this review, we summarize and analyze the current findings in this area, emphasizing the critical role of Ca2+ and mitochondrial metabolism in cancer and its potential as a novel therapeutic target.

RESUMO

Recent evidence highlights that the cancer cell energy requirements vary greatly from normal cells and that cancer cells exhibit different metabolic phenotypes with variable participation of both glycolysis and oxidative phosphorylation. NADH-ubiquinone oxidoreductase (Complex I) is the largest complex of the mitochondrial electron transport chain and contributes about 40% of the proton motive force required for mitochondrial ATP synthesis. In addition, Complex I plays an essential role in biosynthesis and redox control during proliferation, resistance to cell death, and metastasis of cancer cells. Although knowledge about the structure and assembly of Complex I is increasing, information about the role of Complex I subunits in tumorigenesis is scarce and contradictory. Several small molecule inhibitors of Complex I have been described as selective anticancer agents; however, pharmacologic and genetic interventions on Complex I have also shown pro-tumorigenic actions, involving different cellular signaling. Here, we discuss the role of Complex I in tumorigenesis, focusing on the specific participation of Complex I subunits in proliferation and metastasis of cancer cells.