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

Abstract

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.

Caloric Restriction Mimetic 2-Deoxyglucose Reduces Inflammatory Signaling in Human Astrocytes: Implications for Therapeutic Strategies Targeting Neurodegenerative Diseases

“…Chronically reactive astrocytes secrete inflammatory cytokines and may alter blood-brain barrier permeability as well as the uptake of neurotransmitters from extracellular space in a way that contributes to the neurodegenerative process [3][4][5][6][7]14,24,25]. Upon immune stimulation, astrocytes produce inflammatory cytokines and other inflammatory genes including the complement component 3 (C3) [5,26,27].…”

A Non-Canonical Role for IRE1α Links ER and Mitochondria as Key Regulators of Astrocyte Dysfunction: Implications in Methamphetamine use and HIV-Associated Neurocognitive Disorders

“…Moreover, the IRE1α arm has additional stress-associated and non-canonical complexity within the UPRsome. Our group recently published a review highlighting the potential of targeting MAMs in neurodegeneration with specific attention to ER stress, calcium dysregulation, and mitochondrial dysfunction in the context of HAND (Proulx et al, 2021). These MAM-mediated mechanisms are prominent perpetrators underlying neuropathology among others including autophagy, inflammation, and apoptosis.…”

“…Modifications in MAM tethering and activity are implicated in a number of neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis (Area-Gomez et al, 2012;Hedskog et al, 2013;Area-Gomez and Schon, 2017;Erpapazoglou et al, 2017;Rodriguez-Arribas et al, 2017;Leal et al, 2018) but have not yet been investigated in HAND or substance use disorders. Indeed, ER and oxidative stress, mitochondrial dysfunction, and calcium dysregulation are three MAM-associated disturbances that characterize neurodegenerative pathologies (Brown and Naidoo, 2012;Muller et al, 2018), including HAND, which our group recently reviewed (Proulx et al, 2021). The forefront of MAM research in the brain has largely been focused on neurons or whole brain tissues (Hedskog et al, 2013;Erpapazoglou et al, 2017;Rodriguez-Arribas et al, 2017;Leal et al, 2018).…”

Mitochondria-Associated Endoplasmic Reticulum Membranes: Inextricably Linked with Autophagy Process

“…MAMs and autophagy may be targeted in pathogenic infections to undermine host cellular defense mechanisms, according to an underappreciated body of research. In response to HIV-1, MFN2 and Drp1 decreased with the impairment of ER-mitochondrial interaction, and a blockade of autophagy flux was observed [ 96 , 97 ]. Legionella pneumophila secreted a serine protease Lpg1137, localized to the cytosol and the MAMs to degrade syntaxin 17 (STX17) in fed cells [ 98 ].…”