Mitochondria-associated ER Membranes Function Research Articles

Impact of DEHP on mitochondria-associated endoplasmic reticulum membranes and reproductive toxicity in ovary

Di(2-ethylhexyl) phthalate (DEHP) is a widely recognized environmental endocrine disruptor that potentially impacts female reproductive function, although the specific mechanisms leading to such impairment remain unclear. A growing body of research has revealed that the endoplasmic reticulum and mitochondrial function significantly influence oocyte quality. The structure of mitochondria-associated endoplasmic reticulum membranes (MAMs) is crucial for facilitating the exchange of Ca2+, lipids, and metabolites. This study aimed to investigate the alterations in the composition and function of MAMs after DEHP exposure and to elucidate the underlying mechanisms of ovarian toxicity. The female mice were exposed to DEHP at doses of 5 and 500 mg/kg/day for one month. The results revealed that DEHP exposure led to reduced serum anti-Müllerian hormone levels and increased atretic follicles in mice. DEHP induced endoplasmic reticulum stress and disrupted calcium homeostasis in oocytes. Furthermore, DEHP impaired the mitochondrial function of oocytes and reduced their membrane potential, and promoting apoptosis. Similar results were observed in human granulosa cells after exposure to mono-(2-ethylhexyl) phthalate (MEHP, metabolites of DEHP) in vitro. Proteomic analysis and transmission electron microscopy revealed modifications in the functional proteins and structure of the MAMs, and the suppression of oxidative phosphorylation pathways. The findings of this investigation provide a new perspective on the mechanism underlying the reproductive toxicity of DEHP in females.

Aberrant ER-mitochondria communication is a common pathomechanism in mitochondrial disease

Genetic mutations causing primary mitochondrial disease (i.e those compromising oxidative phosphorylation [OxPhos]) resulting in reduced bioenergetic output display great variability in their clinical features, but the reason for this is unknown. We hypothesized that disruption of the communication between endoplasmic reticulum (ER) and mitochondria at mitochondria-associated ER membranes (MAM) might play a role in this variability. To test this, we assayed MAM function and ER-mitochondrial communication in OxPhos-deficient cells, including cybrids from patients with selected pathogenic mtDNA mutations. Our results show that each of the various mutations studied indeed altered MAM functions, but notably, each disorder presented with a different MAM “signature”. We also found that mitochondrial membrane potential is a key driver of ER-mitochondrial connectivity. Moreover, our findings demonstrate that disruption in ER-mitochondrial communication has consequences for cell survivability that go well beyond that of reduced ATP output. The findings of a “MAM-OxPhos” axis, the role of mitochondrial membrane potential in controlling this process, and the contribution of MAM dysfunction to cell death, reveal a new relationship between mitochondria and the rest of the cell, as well as providing new insights into the diagnosis and treatment of these devastating disorders.

TRPV1 Channels Are New Players in the Reticulum-Mitochondria Ca2+ Coupling in a Rat Cardiomyoblast Cell Line.

The Ca2+ release in microdomains formed by intercompartmental contacts, such as mitochondria-associated endoplasmic reticulum membranes (MAMs), encodes a signal that contributes to Ca2+ homeostasis and cell fate control. However, the composition and function of MAMs remain to be fully defined. Here, we focused on the transient receptor potential vanilloid 1 (TRPV1), a Ca2+-permeable ion channel and a polymodal nociceptor. We found TRPV1 channels in the reticular membrane, including some at MAMs, in a rat cardiomyoblast cell line (SV40-transformed H9c2) by Western blotting, immunostaining, cell fractionation, and proximity ligation assay. We used chemical and genetic probes to perform Ca2+ imaging in four cellular compartments: the endoplasmic reticulum (ER), cytoplasm, mitochondrial matrix, and mitochondrial surface. Our results showed that the ER Ca2+ released through TRPV1 channels is detected at the mitochondrial outer membrane and transferred to the mitochondria. Finally, we observed that prolonged TRPV1 modulation for 30 min alters the intracellular Ca2+ equilibrium and influences the MAM structure or the hypoxia/reoxygenation-induced cell death. Thus, our study provides the first evidence that TRPV1 channels contribute to MAM Ca2+ exchanges.

Mitochondria-associated endoplasmic reticulum membranes and cardiac hypertrophy: Molecular mechanisms and therapeutic targets.

Cardiac hypertrophy has been shown to compensate for cardiac performance and improve ventricular wall tension as well as oxygen consumption. This compensatory response results in several heart diseases, which include ischemia disease, hypertension, heart failure, and valvular disease. Although the pathogenesis of cardiac hypertrophy remains complicated, previous data show that dysfunction of the mitochondria and endoplasmic reticulum (ER) mediates the progression of cardiac hypertrophy. The interaction between the mitochondria and ER is mediated by mitochondria-associated ER membranes (MAMs), which play an important role in the pathology of cardiac hypertrophy. The function of MAMs has mainly been associated with calcium transfer, lipid synthesis, autophagy, and reactive oxygen species (ROS). In this review, we discuss key MAMs-associated proteins and their functions in cardiovascular system and define their roles in the progression of cardiac hypertrophy. In addition, we demonstrate that MAMs is a potential therapeutic target in the treatment of cardiac hypertrophy.

Compositions and Functions of Mitochondria-Associated Endoplasmic Reticulum Membranes and Their Contribution to Cardioprotection by Exercise Preconditioning.

Mitochondria-associated endoplasmic reticulum membranes (MAMs) are important components of intracellular signaling and contribute to the regulation of intracellular Ca2+/lipid homeostasis, mitochondrial dynamics, autophagy/mitophagy, apoptosis, and inflammation. Multiple studies have shown that proteins located on MAMs mediate cardioprotection. Exercise preconditioning (EP) has been shown to protect the myocardium from adverse stimuli, but these mechanisms are still being explored. Recently, a growing body of evidence points to MAMs, suggesting that exercise or EP may be involved in cardioprotection by modulating proteins on MAMs and subsequently affecting MAMs. In this review, we summarize the latest findings on MAMs, analyzing the structure and function of MAMs and the role of MAM-related proteins in cardioprotection. We focused on the possible mechanisms by which exercise or EP can modulate the involvement of MAMs in cardioprotection. We found that EP may affect MAMs by regulating changes in MFN2, MFN1, AMPK, FUNDC1, BECN1, VDAC1, GRP75, IP3R, CYPD, GSK3β, AKT, NLRP3, GRP78, and LC3, thus playing a cardioprotective role. We also provided direction for future studies that may be of interest so that more in-depth studies can be conducted to elucidate the relationship between EP and cardioprotection.

309-OR: Lipocalin 2 Deficiency Impairs Mitochondrial Dynamics and Phospholipid Metabolism in Brown Adipocytes

Impaired mitochondrial bioenergetics in brown adipocytes links to the disrupted energy metabolism and thermogenesis in obesity. Phospholipids, particularly cardiolipin and phosphatidic acid (PA) are critical regulators of mitochondrial membrane architecture and dynamics. Mitochondria-associated endoplasmic reticulum membranes (MAMs) serve as the platform for phospholipid biosynthesis. MAM dysfunction disturbs phospholipid metabolism, thereby disrupting mitochondrial function. However, little is known about the participating factors that regulate MAM phospholipid metabolism. We have previously characterized the role of lipocalin 2 (Lcn2) in thermogenesis and mitochondrial function in adipocytes. Herein, we found that Lcn2 was located at MAMs and had a specific PA binding capability. The mitochondrial fusion-fission process induced by the fasting-refeeding cycle was impaired in Lcn2 knockout (KO) brown adipocytes. We also observed that the levels of phosphorylated Drp1 (Ser616) and Opa1 were decreased in brown adipose tissue (BAT) of Lcn2 KO mice compared to WT controls upon acute cold stimulation, whereas Lcn2 overexpression in BAT led to an increase in Drp1 phosphorylation and Opa1 level. Moreover, Lcn2 deficiency significantly enhanced the cold-stimulated accumulation of Opa1 as well as MAM markers SigmaR1, Ip3R1, and Facl4 at MAMs in BAT, suggesting impaired MAM function. CL316,243, a β3-adrenergic receptor agonist has a cold mimic effect on mitochondrial bioenergetics. In brown adipocytes, Lcn2 deficiency significantly attenuated the CL316,243 induction of Drp1 phosphorylation. Intriguingly, lipidomic analysis of BAT mitochondria isolated from mice treated with CL316,243 for 14 days showed that Lcn2 deficiency blunted CL316,243-induced cardiolipin biosynthesis and altered phospholipid metabolism. Together, we discovered a role of Lcn2 as a novel PA transfer protein in mitochondrial bioenergetics via regulating phospholipid metabolism. Disclosure H.Su: None. H.Guo: None. X.Qiu: None. T.Lin: None. X.Chen: None. Funding This work was supported by NIDDK Grant (RDK123042) awarded to Xiaoli Chen.

Mitochondria-Endoplasmic Reticulum Contacts: The Promising Regulators in Diabetic Cardiomyopathy.

Diabetic cardiomyopathy (DCM), as a serious complication of diabetes, causes structural and functional abnormalities of the heart and eventually progresses to heart failure. Currently, there is no specific treatment for DCM. Studies have proved that mitochondrial dysfunction and endoplasmic reticulum (ER) stress are key factors for the development and progression of DCM. The mitochondria-associated ER membranes (MAMs) are a unique domain formed by physical contacts between mitochondria and ER and mediate organelle communication. Under high glucose conditions, changes in the distance and composition of MAMs lead to abnormal intracellular signal transduction, which will affect the physiological function of MAMs, such as alter the Ca2+ homeostasis in cardiomyocytes, and lead to mitochondrial dysfunction and abnormal apoptosis. Therefore, the dysfunction of MAMs is closely related to the pathogenesis of DCM. In this review, we summarized the evidence for the role of MAMs in DCM and described that MAMs participated directly or indirectly in the regulation of the pathophysiological process of DCM via the regulation of Ca2+ signaling, mitochondrial dynamics, ER stress, autophagy, and inflammation. Finally, we discussed the clinical transformation prospects and technical limitations of MAMs-associated proteins (such as MFN2, FUNDC1, and GSK3β) as potential therapeutic targets for DCM.

Activation of the sigma-1 receptor chaperone alleviates symptoms of Wolfram syndrome in preclinical models.

The Wolfram syndrome is a rare autosomal recessive disease affecting many organs with life-threatening consequences; currently, no treatment is available. The disease is caused by mutations in the WSF1 gene, coding for the protein wolframin, an endoplasmic reticulum (ER) transmembrane protein involved in contacts between ER and mitochondria termed as mitochondria-associated ER membranes (MAMs). Inherited mutations usually reduce the protein's stability, altering its homeostasis and ultimately reducing ER to mitochondria calcium ion transfer, leading to mitochondrial dysfunction and cell death. In this study, we found that activation of the sigma-1 receptor (S1R), an ER-resident protein involved in calcium ion transfer, could counteract the functional alterations of MAMs due to wolframin deficiency. The S1R agonist PRE-084 restored calcium ion transfer and mitochondrial respiration in vitro, corrected the associated increased autophagy and mitophagy, and was able to alleviate the behavioral symptoms observed in zebrafish and mouse models of the disease. Our findings provide a potential therapeutic strategy for treating Wolfram syndrome by efficiently boosting MAM function using the ligand-operated S1R chaperone. Moreover, such strategy might also be relevant for other degenerative and mitochondrial diseases involving MAM dysfunction.

Cal'MAM'ity at the Endoplasmic Reticulum-Mitochondrial Interface: A Potential Therapeutic Target for Neurodegeneration and Human Immunodeficiency Virus-Associated Neurocognitive Disorders.

The endoplasmic reticulum (ER) is a multifunctional organelle and serves as the primary site for intracellular calcium storage, lipid biogenesis, protein synthesis, and quality control. Mitochondria are responsible for producing the majority of cellular energy required for cell survival and function and are integral for many metabolic and signaling processes. Mitochondria-associated ER membranes (MAMs) are direct contact sites between the ER and mitochondria that serve as platforms to coordinate fundamental cellular processes such as mitochondrial dynamics and bioenergetics, calcium and lipid homeostasis, autophagy, apoptosis, inflammation, and intracellular stress responses. Given the importance of MAM-mediated mechanisms in regulating cellular fate and function, MAMs are now known as key molecular and cellular hubs underlying disease pathology. Notably, neurons are uniquely susceptible to mitochondrial dysfunction and intracellular stress, which highlights the importance of MAMs as potential targets to manipulate MAM-associated mechanisms. However, whether altered MAM communication and connectivity are causative agents or compensatory mechanisms in disease development and progression remains elusive. Regardless, exploration is warranted to determine if MAMs are therapeutically targetable to combat neurodegeneration. Here, we review key MAM interactions and proteins both in vitro and in vivo models of Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis. We further discuss implications of MAMs in HIV-associated neurocognitive disorders (HAND), as MAMs have not yet been explored in this neuropathology. These perspectives specifically focus on mitochondrial dysfunction, calcium dysregulation and ER stress as notable MAM-mediated mechanisms underlying HAND pathology. Finally, we discuss potential targets to manipulate MAM function as a therapeutic intervention against neurodegeneration. Future investigations are warranted to better understand the interplay and therapeutic application of MAMs in glial dysfunction and neurotoxicity.

Mitochondria-Associated Endoplasmic Reticulum Membranes in Cardiovascular Diseases.

The endoplasmic reticulum (ER) and mitochondria are physically connected to form dedicated structural domains known as mitochondria-associated ER membranes (MAMs), which participate in fundamental biological processes, including lipid and calcium (Ca2+) homeostasis, mitochondrial dynamics and other related cellular behaviors such as autophagy, ER stress, inflammation and apoptosis. Many studies have proved the importance of MAMs in maintaining the normal function of both organelles, and the abnormal amount, structure or function of MAMs is related to the occurrence of cardiovascular diseases. Here, we review the knowledge regarding the components of MAMs according to their different functions and the specific roles of MAMs in cardiovascular physiology and pathophysiology, focusing on some highly prevalent cardiovascular diseases, including ischemia-reperfusion, diabetic cardiomyopathy, heart failure, pulmonary arterial hypertension and systemic vascular diseases. Finally, we summarize the possible mechanisms of MAM in cardiovascular diseases and put forward some obstacles in the understanding of MAM function we may encounter.

Mitochondria-associated ER membranes in glucose homeostasis and insulin resistance.

Obesity and insulin resistance (IR) are associated with endoplasmic reticulum (ER) stress and mitochondrial dysfunction in several tissues. Although for many years mitochondrial and ER function were studied separately, these organelles also connect to produce interdependent functions. Communication occurs at mitochondria-associated ER membranes (MAMs) and regulates lipid and calcium homeostasis, apoptosis, and the exchange of adenine nucleotides, among other things. Recent evidence suggests that MAMs contribute to organelle, cellular, and systemic metabolism. In obesity and IR models, metabolic tissues such as the liver, skeletal muscle, pancreas, and adipose tissue present alterations in MAM structure or function. The purpose of this mini review is to highlight the MAM disruptions that occur in each tissue during obesity and IR and its relationship with glucose homeostasis and IR. We also discuss the current controversy that surrounds MAMs' role in the development of IR.

Mitochondria-Associated ER Membranes - The Origin Site of Autophagy.

Autophagy is a process of intracellular self-recycling and degradation that plays an important role in maintaining cell homeostasis. However, the molecular mechanism of autophagy remains to be further studied. Mitochondria-associated endoplasmic reticulum membranes (MAMs) are the region of the ER that mediate communication between the ER and mitochondria. MAMs have been demonstrated to be involved in autophagy, Ca2+ transport and lipid metabolism. Here, we discuss the composition and function of MAMs, more specifically, to emphasize the role of MAMs in regulating autophagy. Finally, some key information that may be useful for future research is summarized.

Mitochondria in alzheimer’s disease

The pathogenesis of Alzheimer disease (AD) is associated with aberrant proteolytic processing of the amyloid precursor protein (APP) - first by b-secretase to generate a 99-aa C-terminal fragment (C99) and then by g-secretase (containing presenilins-1 [PS1] or -2 [PS2]) that cleaves C99 to generate the APP intracellular domain and the b-amyloid (Ab) that is found in extraneuronal plaques - but the relationship of the former to the latter is unclear. Whereas plaques typically form late in disease progression, early events include aberrant lipid metabolism and mitochondrial dysfunction. We recently showed that PS1, PS2, and g-secretase activity itself are highly enriched in a subdomain of the endoplasmic reticulum (ER) that communicates with mitochondria, called mitochondria-associated ER membranes (MAM), and that ER-mitochondrial connectivity and MAM function are highly upregulated in presenilin-mutant cells and in cells from AD patients. However, the relationship of perturbed APP processing to MAM-related AD phenotypes has been unclear. MAM, which is a lipid raft rich in cholesterol and sphingomyelin, is a key regulator of lipid metabolism and of mitochondial dynamics, among other processes. We now show that C99 is highly enriched in the MAM, and that it plays a central role in regulating cellular cholesterol and sphingolipid homeostasis and mitochondrial bioenergetics. Furthermore, in cells from AD patients and in cell and animal models of AD, C99 levels are increased significantly, resulting in a disruption of lipid homeostasis that is triggered by the unregulated uptake of extracellular cholesterol, with downstream consequences that mimic the biochemical features of AD, including the bioenergetic deficits. We propose that MAM-localized C99 is a component of the cell's lipid sensing machinery and that its accumulation is a key and early event in AD pathogenesis that can explain many of the biochemical and morphological features of the disease.

MFN2 mutations in Charcot-Marie-Tooth disease alter mitochondria-associated ER membrane function but do not impair bioenergetics.

Charcot–Marie–Tooth disease (CMT) type 2A is a form of peripheral neuropathy, due almost exclusively to dominant mutations in the nuclear gene encoding the mitochondrial protein mitofusin-2 (MFN2). However, there is no understanding of the relationship of clinical phenotype to genotype. MFN2 has two functions: it promotes inter-mitochondrial fusion and mediates endoplasmic reticulum (ER)–mitochondrial tethering at mitochondria-associated ER membranes (MAM). MAM regulates a number of key cellular functions, including lipid and calcium homeostasis, and mitochondrial behavior. To date, no studies have been performed to address whether mutations in MFN2 in CMT2A patient cells affect MAM function, which might provide insight into pathogenesis. Using fibroblasts from three CMT2AMFN2 patients with different mutations in MFN2, we found that some, but not all, examined aspects of ER–mitochondrial connectivity and of MAM function were indeed altered, and correlated with disease severity. Notably, however, respiratory chain function in those cells was unimpaired. Our results suggest that CMT2AMFN2 is a MAM-related disorder but is not a respiratory chain-deficiency disease. The alterations in MAM function described here could also provide insight into the pathogenesis of other forms of CMT.

On the Pathogenesis of Alzheimer's Disease: The MAM Hypothesis

The pathogenesis of Alzheimer's disease (AD) is currently unclear and is the subject of much debate. The most widely accepted hypothesis designed to explain AD pathogenesis is the amyloid cascade, which invokes the accumulation of extracellular plaques and intracellular tangles as playing a fundamental role in the course and progression of the disease. However, besides plaques and tangles, other biochemical and morphological features are also present in AD, often manifesting early in the course of the disease before the accumulation of plaques and tangles. These include altered calcium, cholesterol, and phospholipid metabolism; altered mitochondrial dynamics; and reduced bioenergetic function. Notably, these other features of AD are associated with functions localized to a subdomain of the endoplasmic reticulum (ER), known as mitochondria-associated ER membranes (MAMs). The MAM region of the ER is a lipid raft-like domain closely apposed to mitochondria in such a way that the 2 organelles are able to communicate with each other, both physically and biochemically, thereby facilitating the functions of this region. We have found that MAM-localized functions are increased significantly in cellular and animal models of AD and in cells from patients with AD in a manner consistent with the biochemical findings noted above. Based on these and other observations, we propose that increased ER-mitochondrial apposition and perturbed MAM function lie at the heart of AD pathogenesis.-Area-Gomez, E., Schon, E. A. On the pathogenesis of Alzheimer's disease: the MAM hypothesis.

Alzheimer Disease.

The most widely accepted hypothesis to explain the pathogenesis of Alzheimer disease (AD) is the amyloid cascade, in which the accumulation of extraneuritic plaques and intracellular tangles plays a key role in driving the course and progression of the disease. However, there are other biochemical and morphological features of AD, including altered calcium, phospholipid, and cholesterol metabolism and altered mitochondrial dynamics and function that often appear early in the course of the disease, prior to plaque and tangle accumulation. Interestingly, these other functions are associated with a subdomain of the endoplasmic reticulum (ER) called mitochondria-associated ER membranes (MAM). MAM, which is an intracellular lipid raft-like domain, is closely apposed to mitochondria, both physically and biochemically. These MAM-localized functions are, in fact, increased significantly in various cellular and animal models of AD and in cells from AD patients, which could help explain the biochemical and morphological alterations seen in the disease. Based on these and other observations, a strong argument can be made that increased ER-mitochondria connectivity and increased MAM function are fundamental to AD pathogenesis.

Role of mitochondrial dysfunction and dysregulation of Ca(2+) homeostasis in insulin insensitivity of mammalian cells.

Mitochondria and endoplasmic reticulum (ER) play an important role in the maintenance of intracellular Ca(2+) homeostasis, and their defects may be etiological factors contributing to insulin resistance and type 2 diabetes (T2D). Recent studies indicate that alterations of Ca(2+) levels and Ca(2+) -dependent signaling pathways can impede the insulin signaling cascade, resulting in insulin resistance of β cells and insulin-responsive cells. Mitochondria-associated ER membranes (MAMs) are essential for efficient communication between the ER and mitochondria. Thus, abnormalities in the structure and function of MAMs in affected tissue cells in T2D are an important area of study. Recently, we demonstrated that a deficiency of Cisd2, an iron-sulfur protein localized on MAMs, could lead to mitochondrial dysfunction and disturbance of intracellular Ca(2+) homeostasis. Moreover, we first elucidated that defects in the function of MAMs in Ca(2+) uptake resulted in insulin insensitivity of adipocytes, which plays an important role in the pathogenesis of diabetes in Cisd2 knockout mice. On the basis of these observations, we suggest improving the bioenergetic function of mitochondria and the function of MAMs in maintaining Ca(2+) homeostasis as a novel strategy for the development of new therapeutics aimed at preventing and treating insulin resistance and T2D.

Modulation of the endoplasmic reticulum–mitochondria interface in Alzheimer’s disease and related models

It is well-established that subcompartments of endoplasmic reticulum (ER) are in physical contact with the mitochondria. These lipid raft-like regions of ER are referred to as mitochondria-associated ER membranes (MAMs), and they play an important role in, for example, lipid synthesis, calcium homeostasis, and apoptotic signaling. Perturbation of MAM function has previously been suggested in Alzheimer's disease (AD) as shown in fibroblasts from AD patients and a neuroblastoma cell line containing familial presenilin-2 AD mutation. The effect of AD pathogenesis on the ER-mitochondria interplay in the brain has so far remained unknown. Here, we studied ER-mitochondria contacts in human AD brain and related AD mouse and neuronal cell models. We found uniform distribution of MAM in neurons. Phosphofurin acidic cluster sorting protein-2 and σ1 receptor, two MAM-associated proteins, were shown to be essential for neuronal survival, because siRNA knockdown resulted in degeneration. Up-regulated MAM-associated proteins were found in the AD brain and amyloid precursor protein (APP)Swe/Lon mouse model, in which up-regulation was observed before the appearance of plaques. By studying an ER-mitochondria bridging complex, inositol-1,4,5-triphosphate receptor-voltage-dependent anion channel, we revealed that nanomolar concentrations of amyloid β-peptide increased inositol-1,4,5-triphosphate receptor and voltage-dependent anion channel protein expression and elevated the number of ER-mitochondria contact points and mitochondrial calcium concentrations. Our data suggest an important role of ER-mitochondria contacts and cross-talk in AD pathology.

Mitochondria-associated ER membranes in Alzheimer disease

Alzheimer disease (AD) is associated with the accumulation in the brain of extracellular neuritic plaques composed mainly of β-amyloid (Aβ) and of intracellular neurofibrillary tangles composed of hyperphosphorylated forms of the microtubule-associated protein tau. It is also associated with other features that have received less attention, including aberrant phospholipid, cholesterol, and calcium metabolism, and altered mitochondrial function and dynamics. The underlying mechanism(s) that might explain these observations are currently unknown. We recently showed that presenilin-1 (PS1), presenilin-2 (PS2), and γ-secretase activity, which processes the amyloid precursor protein (APP) to generate Aβ, are located predominantly in a specialized subcompartment of the endoplasmic reticulum (ER) that is physically and biochemically connected to mitochondria, called mitochondria-associated ER membranes (MAM). MAM is an intracellular lipid raft-like structure intimately involved in cholesterol and phospholipid lipid metabolism, in calcium homeostasis, and in mitochondrial function and dynamics. The coincidence of the functions associated with MAM with the symptomatology of AD led us to speculate that presenilins play a role in maintaining MAM function. We found that, consistent with this supposition, both MAM function and ER-mitochondrial connectivity are increased significantly in AD, which may help explain many of the biochemical and morphological features of the disease. Based on these findings, we propose that AD is fundamentally a disorder of ER-mitochondrial communication (the "MAM hypothesis"). This article is part of a Special Issue entitled 'Mitochondrial function and dysfunction in neurodegeneration'.

Upregulated function of mitochondria-associated ER membranes in Alzheimer disease

Alzheimer disease (AD) is associated with aberrant processing of the amyloid precursor protein (APP) by γ-secretase, via an unknown mechanism. We recently showed that presenilin-1 and -2, the catalytic components of γ-secretase, and γ-secretase activity itself, are highly enriched in a subcompartment of the endoplasmic reticulum (ER) that is physically and biochemically connected to mitochondria, called mitochondria-associated ER membranes (MAMs). We now show that MAM function and ER-mitochondrial communication-as measured by cholesteryl ester and phospholipid synthesis, respectively-are increased significantly in presenilin-mutant cells and in fibroblasts from patients with both the familial and sporadic forms of AD. We also show that MAM is an intracellular detergent-resistant lipid raft (LR)-like domain, consistent with the known presence of presenilins and γ-secretase activity in rafts. These findings may help explain not only the aberrant APP processing but also a number of other biochemical features of AD, including altered lipid metabolism and calcium homeostasis. We propose that upregulated MAM function at the ER-mitochondrial interface, and increased cross-talk between these two organelles, may play a hitherto unrecognized role in the pathogenesis of AD.