Molecular Dysfunctions of Mitochondria-Associated Membranes (MAMs) in Alzheimer's Disease

Abstract

Alzheimer's disease (AD) is a multifactorial neurodegenerative pathology characterized by a progressive decline of cognitive functions. Alteration of various signaling cascades affecting distinct subcellular compartment functions and their communication likely contribute to AD progression. Among others, the alteration of the physical association between the endoplasmic reticulum (ER) and mitochondria, also reffered as mitochondria-associated membranes (MAMs), impacts various cellular housekeeping functions such as phospholipids-, glucose-, cholesterol-, and fatty-acid-metabolism, as well as calcium signaling, which are all altered in AD. Our review describes the physical and functional proteome crosstalk between the ER and mitochondria and highlights the contribution of distinct molecular components of MAMs to mitochondrial and ER dysfunctions in AD progression. We also discuss potential strategies targeting MAMs to improve mitochondria and ER functions in AD.

Keywords: APOE; APP-C-terminal fragments (APP-CTFs); Alzheimer’s disease (AD); Amyloid β peptide (Aβ); Endoplasmic Reticulum (ER); Mitochondria-Associated Membranes (MAMs); Unfolded Protein Response (UPR); calcium signaling; cholesterol; fatty acid; lipids; mitochondria; phospholipids; tau; unfolded protein response; β amyloid precursor protein (APP).

Figure 2

Schema showing the localization and alterations of MAMs molecular components in AD, including upregulation (↑) or down-regulation (↓) of MAMs proteins expression, MAMs proteins interactions (⟷), and genes polymorphism.

Figure 3

APP and its derived fragments APP-CTFs and Aβ; presenilins (PSs), pTau and APOE4 are involved in the impairment of the expression and activity of several mitochondrial proteins (highlighted in red) and interfere with UPR in the ER. APP localizes and is processed by β- and γ-secretases in MAMs. AD Molecular partners also disturb MAMs structure and function.

Figure 1

Bidirectional regulation of ER and mitochondria functions in MAMs. Mitochondria Ca²⁺ uptake (i.e., by the VDAC (voltage-dependent anion channel) located in the outer mitochondria membrane (OMM) and the mitochondrial Ca²⁺ uniporter complex (MCU) located in the inner mitochondria membrane (IMM)) increases the activity of mitochondrial enzymes (i.e., the pyruvate dehydrogenase (PDH), and the tricarboxylic acid cycle (TCA)) orchestrating the activity of the oxidative phosphorylation electron transport chain (ETC) producing ATP by the F1F0 ATP-synthase. ATP is then transported through the adenine nucleotide translocator (ANT). In return, ATP is used by the sarco-endoplasmic reticulum Ca²⁺ ATPase (SERCA) ensuring active Ca²⁺ storage in the ER, necessary for ER functions (i.e., protein synthesis and maturation). Mitochondrial Ca²⁺ homeostasis results from an equilibrium between Ca²⁺ uptake and extrusion by the Na²⁺/Ca²⁺ exchanger (NCX). Prolonged or excessive mitochondrial Ca²⁺ uptake triggers mitochondrial membrane permeability transition pore (PTP) opening, initiating cytochrome c (Cyt c) release, apoptosome formation, and the activation of apoptotic cell death. In particular, altered ER Ca²⁺ homeostasis is associated with the unfolded protein response (UPR), triggering excessive transfer of Ca²⁺ from the ER to mitochondria (i.e., through SERCA1 truncated isoform (S1T), or the inositol 1,4,5-trisphosphate receptors (IP₃R)), which is tightly linked to ER stress-mediated mitochondria apoptotic cell death. In parallel, MAMs control phospholipids biosynthesis and transfer between organelles where phosphatidylcholine (PC); phosphatidylethanolamine (PE); and phosphatidylserine (PS) are the most abundant ones. MAMs are also the intersection site of transport and metabolism of cholesterol (Chol), which is catalyzed to generate pregnenolone (Preg) and released to the ER to produce progesterone (Prog). MAMs-associated lipid microdomains regulate the autophagic/mitophagic processes through the recruitment of autophagic proteins and autophagosome formation.