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During the past few decades, considerable efforts have been made to discover and validate new molecular mechanisms and biomarkers of neurodegenerative diseases. Recent discoveries have demonstrated how autophagy and its specialized form mitophagy are extensively associated with the development, maintenance, and progression of several neurodegenerative diseases. These mechanisms play a pivotal role in the homeostasis of neural cells and are responsible for the clearance of intracellular aggregates and misfolded proteins and the turnover of organelles, in particular, mitochondria. In this review, we summarize recent advances describing the importance of autophagy and mitophagy in neurodegenerative diseases, with particular attention given to multiple sclerosis, Parkinson’s disease, and Alzheimer’s disease. We also review how elements involved in autophagy and mitophagy may represent potential biomarkers for these common neurodegenerative diseases. Finally, we examine the possibility that the modulation of autophagic and mitophagic mechanisms may be an innovative strategy for overcoming neurodegenerative conditions. A deeper knowledge of autophagic and mitophagic mechanisms could facilitate diagnosis and prognostication as well as accelerate the development of therapeutic strategies for neurodegenerative diseases.

Mitochondria are dynamic organelles that participate in a broad array of molecular functions within the cell. They are responsible for maintaining the appropriate energetic levels and control the cellular homeostasis throughout the generation of intermediary metabolites. Preserving a healthy and functional mitochondrial population is of fundamental importance throughout the life of the cells under pathophysiological conditions. Hence, cells have evolved fine-tuned mechanisms of quality control that help to preserve the right amount of functional mitochondria to meet the demand of the cell. The specific recycling of mitochondria by autophagy, termed mitophagy, represents the primary contributor to mitochondrial quality control. During this process, damaged or unnecessary mitochondria are recognized and selectively degraded. In the past few years, the knowledge in mitophagy has seen rapid progress, and a growing body of evidence confirms that mitophagy holds a central role in controlling cellular functions and the progression of various human diseases.In this chapter, we will discuss the pathophysiological roles of mitophagy and provide a general overview of the current methods used to monitor and quantify mitophagy. We will also outline the main established approaches to investigate the mitochondrial function, metabolism, morphology, and protein damage.

Calcium ions (Ca2+) and the complex regulatory system governed by Ca2+ signaling have been described to be of crucial importance in numerous aspects related to cell life and death decisions, especially in recent years. The growing attention given to this second messenger is justified by the pleiotropic nature of Ca2+-binding proteins and transporters and their consequent involvement in cell fate decisions. A growing number of works highlight that deregulation of Ca2+ signaling and homoeostasis is often deleterious and drives pathological conditions; in particular, a disruption of the main Ca2+-mediated death mechanisms may lead to uncontrolled cell growth that results in cancer. In this work, we review the latest useful evidence to better understand the complex network of pathways by which Ca2+ regulates cell life and death decisions.

As pivotal players in cellular metabolism, mitochondria have a double-faceted role in the final decision of cell fate. This is true for all cell types, but it is even more important and intriguing in the cancer setting. Mitochondria regulate cell fate in many diverse ways: through metabolism, by producing ATP and other metabolites deemed vital or detrimental for cancer cells; through the regulation of Ca2+ homeostasis, especially by the joint participation of the endoplasmic reticulum in a membranous tethering system for Ca2+ signaling called mitochondria-ER associated membranes (MAMs); and by regulating signaling pathways involved in the survival of cancer cells such as mitophagy. Recent studies have shown that mitochondria can also play a role in the regulation of inflammatory pathways in cancer cells, for example, through the release of mitochondrial DNA (mtDNA) involved in the activation of the cGAS-cGAMP-STING pathway. In this review, we aim to explore the role of mitochondria as decision makers in fostering cancer cell death or survival depending on the tumor cell stage and describe novel anticancer therapeutic strategies targeting mitochondria.

Endoplasmic reticulum (ER)-mitochondria regions are specialized subdomains called also mitochondria-associated membranes (MAMs). MAMs allow regulation of lipid synthesis and represent hubs for ion and metabolite signaling. As these two organelles can module both the amplitude and the spatiotemporal patterns of calcium (Ca2+) signals, this particular interaction controls several Ca2+-dependent pathways well known for their contribution to tumorigenesis, such as metabolism, survival, sensitivity to cell death, and metastasis. Mitochondria-mediated apoptosis arises from mitochondrial Ca2+ overload, permeabilization of the mitochondrial outer membrane, and the release of mitochondrial apoptotic factors into the cytosol. Decreases in Ca2+ signaling at the ER-mitochondria interface are being studied in depth as failure of apoptotic-dependent cell death is one of the predominant characteristics of cancer cells. However, some recent papers that linked MAMs Ca2+ crosstalk-related upregulation to tumor onset and progression have aroused the interest of the scientific community.In this review, we will describe how different MAMs-localized proteins modulate the effectiveness of Ca2+-dependent apoptotic stimuli by causing both increases and decreases in the ER-mitochondria interplay and, specifically, by modulating Ca2+ signaling.

Wolfram syndrome (WS) is a recessive multisystem disorder defined by the association of diabetes mellitus and optic atrophy, reminiscent of mitochondrial diseases. The role played by mitochondria remains elusive, with contradictory results on the occurrence of mitochondrial dysfunction. We evaluated 13 recessive WS patients by deep clinical phenotyping, including optical coherence tomography (OCT), serum lactic acid at rest and after standardized exercise, brain Magnetic Resonance Imaging, and brain and muscle Magnetic Resonance Spectroscopy (MRS). Finally, we investigated mitochondrial bioenergetics, network morphology, and calcium handling in patient-derived fibroblasts. Our results do not support a primary mitochondrial dysfunction in WS patients, as suggested by MRS studies, OCT pattern of retinal nerve fiber layer loss, and, in fibroblasts, by mitochondrial bioenergetics and network morphology results. However, we clearly found calcium mishandling between endoplasmic reticulum (ER) and mitochondria, which, under specific metabolic conditions of increased energy requirements and in selected tissue or cell types, may turn into a secondary mitochondrial dysfunction. Critically, we showed that Wolframin (WFS1) protein is enriched at mitochondrial-associated ER membranes and that in patient-derived fibroblasts WFS1 protein is completely absent. These findings support a loss-of-function pathogenic mechanism for missense mutations in WFS1, ultimately leading to defective calcium influx within mitochondria.

Mitochondria-associated membranes are juxtaposed between the endoplasmic reticulum and mitochondria and have been identified as a critical hub in the regulation of apoptosis and tumor growth. One key function of mitochondria-associated membranes is to provide asylum to a number of proteins with tumor suppressor and oncogenic properties. In this review, we discuss how Ca2+ flux manipulation represents the primary mechanism underlying the action of several oncogenes and tumor-suppressor genes and how these networks might be manipulated to provide novel therapies for cancer. This article is part of a Special Issue entitled: ECS Meeting edited by Claus Heizmann, Joachim Krebs and Jacques Haiech.

International audience; Communication between the endoplasmic reticulum (ER) and mitochondria plays a pivotal role in Ca2+ signaling, energy metabolism, and cell survival. Dysfunction in this cross-talk leads to metabolic and neurodegenerative diseases. Wolfram syndrome is a fatal neurodegenerative disease caused by mutations in the ER-resident protein WFS1. Here, we showed that WFS1 formed a complex with neuronal calcium sensor 1 (NCS1) and inositol 1,4,5-trisphosphate receptor (IP3R) to promote Ca2+ transfer between the ER and mitochondria. In addition, we found that NCS1 abundance was reduced in WFS1-null patient fibroblasts, which showed reduced ER-mitochondria interactions and Ca2+ exchange. Moreover, in WFS1-deficient cells, NCS1 overexpression not only restored ER-mitochondria interactions and Ca2+ transfer but also rescued mitochondrial dysfunction. Our results describe a key role of NCS1 in ER-mitochondria cross-talk, uncover a pathogenic mechanism for Wolfram syndrome, and potentially reveal insights into the pathogenesis of other neurodegenerative diseases.

Mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs) are highly specialized subcellular compartments that are shaped by ER subdomains juxtaposed to mitochondria but are biochemically distinct from pure ER and pure mitochondria. MAMs are enriched in enzymes involved in lipid synthesis and transport, channels for calcium transfer, and proteins with oncogenic/oncosuppressive functions that modulate cell signaling pathways involved in physiological and pathophysiological processes. The term "cancer" denotes a group of disorders that result from uncontrolled cell growth driven by a mixture of genetic and environmental components. Alterations in MAMs are thought to account for the onset as well as the progression and metastasis of cancer and have been a focus of investigation in recent years. In this review, we present the current state of the art regarding MAM-resident proteins and their relevance, alterations, and deregulating functions in different types of cancer from a cell biology and clinical perspective. ispartof: Neoplasia vol:20 issue:5 pages:510-523 ispartof: location:United States status: published

Calcium (Ca2+) is considered one of the most-important biological cations, because it is implicated in cell physiopathology and cell fate through a finely tuned signaling system. In support of this notion, Ca2+ is the primary driver of cell proliferation and cell growth; however, it is also intimately linked to cell death. Functional abnormalities or mutations in proteins that mediate Ca2+ homeostasis usually lead to a plethora of diseases and pathogenic states, including cancer, heart failure, diabetes, and neurodegenerative disease. In this review, we examine recent discoveries in the highly localized nature of Ca2+-dependent signal transduction and its roles in cell fate, inflammasome activation, and synaptic transmission.

BRCA1-associated protein 1 (BAP1) is a potent tumour suppressor gene that modulates environmental carcinogenesis. All carriers of inherited heterozygous germline BAP1-inactivating mutations (BAP1 +/-) developed one and often several BAP1 -/- malignancies in their lifetime, mostly malignant mesothelioma, uveal melanoma, and so on. Moreover, BAP1-acquired biallelic mutations are frequent in human cancers. BAP1 tumour suppressor activity has been attributed to its nuclear localization, where it helps to maintain genome integrity. The possible activity of BAP1 in the cytoplasm is unknown. Cells with reduced levels of BAP1 exhibit chromosomal abnormalities and decreased DNA repair by homologous recombination, indicating that BAP1 dosage is critical. Cells with extensive DNA damage should die and not grow into malignancies. Here we discover that BAP1 localizes at the endoplasmic reticulum. Here, it binds, deubiquitylates, and stabilizes type 3 inositol-1,4,5-trisphosphate receptor (IP3R3), modulating calcium (Ca 2+) release from the endoplasmic reticulum into the cytosol and mitochondria, promoting apoptosis. Reduced levels of BAP1 in BAP1 +/- carriers cause reduction both of IP3R3 levels and of Ca 2+ flux, preventing BAP1 +/- cells that accumulate DNA damage from executing apoptosis. A higher fraction of cells exposed to either ionizing or ultraviolet radiation, or to asbestos, survive genotoxic stress, resulting in a higher rate of cellular transformation. We propose that the high incidence of cancers in BAP1 +/- carriers results from the combined reduced nuclear and cytoplasmic activities of BAP1. Our data provide a mechanistic rationale for the powerful ability of BAP1 to regulate gene-environment interaction in human carcinogenesis.

The mitochondrial aspartate-glutamate carrier isoform 1 (AGC1) catalyzes a Ca2+-stimulated export of aspartate to the cytosol in exchange for glutamate, and is a key component of the malate-aspartate shuttle which transfers NADH reducing equivalents from the cytosol to mitochondria. By sustaining the complete glucose oxidation, AGC1 is thought to be important in providing energy for cells, in particular in the CNS and muscle where this protein is mainly expressed. Defects in the AGC1 gene cause AGC1 deficiency, an infantile encephalopathy with delayed myelination and reduced brain N-acetylaspartate (NAA) levels, the precursor of myelin synthesis in the CNS. Here, we show that undifferentiated Neuro2A cells with down-regulated AGC1 display a significant proliferation deficit associated with reduced mitochondrial respiration, and are unable to synthesize NAA properly. In the presence of high glutamine oxidation, cells with reduced AGC1 restore cell proliferation, although oxidative stress increases and NAA synthesis deficit persists. Our data suggest that the cellular energetic deficit due to AGC1 impairment is associated with inappropriate aspartate levels to support neuronal proliferation when glutamine is not used as metabolic substrate, and we propose that delayed myelination in AGC1 deficiency patients could be attributable, at least in part, to neuronal loss combined with lack of NAA synthesis occurring during the nervous system development.

Until 1972, the term 'apoptosis' was used to differentiate the programmed cell death that naturally occurs in organismal development from the acute tissue death referred to as necrosis. Many studies on cell death and programmed cell death have been published and most are, at least to some degree, related to cancer. Some key proteins and molecular pathways implicated in cell death have been analyzed, whereas others are still being actively researched; therefore, an increasing number of cellular compartments and organelles are being implicated in cell death and cancer. Here, we discuss the mitochondria and subdomains of the endoplasmic reticulum (ER) that interact with mitochondria, the mitochondria-associated membranes (MAMs), which have been identified as critical hubs in the regulation of cell death and tumor growth. MAMs-dependent calcium (Ca2+) release from the ER allows selective Ca2+ uptake by the mitochondria. The perturbation of Ca2+ homeostasis in cancer cells is correlated with sustained cell proliferation and the inhibition of cell death through the modulation of Ca2+ signaling. This article is part of a Special Issue entitled Mitochondria in Cancer, edited by Giuseppe Gasparre, Rodrigue Rossignol and Pierre Sonveaux.