The role of mitochondria-associated ER membranes (MAM) in cellular homeostasis

Web Lab: Estela Area Gómez

My laboratory currently has three major research goals:

1. To understand the role of mitochondria-associated ER membranes (MAM) in the overall lipid homeostasis of neurons.
2. To understand whether perturbations in mitochondria-associated ER membranes (MAM) and lipid signaling underlie synaptic dysfunction and/or neuronal death in various disorders, including Alzheimer's disease and Amyotrophic Lateral Sclerosis.
3. To identify lipid biomarkers that either segregate with or predict clinical outcomes of neurological disorders, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis and Down syndrome.

To tackle these fundamental questions, my lab employs multidisciplinary approaches, which range from molecular and cell biology, protein, and lipid biochemistry (including state-of-the-art ‘lipidomics’-based approaches) to mouse genetics and behavioral assessments of genetically-modified mice.

In the last decade, our concept of cell architecture has progressively changed, from the classic image where the different organelles were floating independently in the cytosol, to a cell where all the organelles interact with each other, forming functional contact sites. in membranes [3]. These membrane-to-membrane contacts are proposed in the field as a form of communication between different organelles and with previously unsuspected relevance to cell function. For example, functions such as the  calcium transport, the regulation of lipid synthesis and transport or the formation of autophagosomes are located in areas of contact between organelles such as the ER, mitochondria, Golgi or peroxisomes [3].

One of the most studied interactions in the field is what happens between the endoplasmic reticulum (ER) and mitochondria, whose contact results in the formation of cholesterol-rich domains (or lipid-rafts) in the ER, called MAMs (mitochondria associated membranes).

Among other functions, MAM has been related to the synthesis of phospholipids, cholesterol transport and regulation of glucose metabolism and calcium transport [5-8].

The study of the role of MAM in cell regulation has expanded remarkably in the last 5 years with numerous works focused on the study of the protein composition of MAM or the generation of genetic tools to induce  union of both organelles [9]. On the other hand, the role of MAM in metabolic and neurodegenerative diseases such as diabetes or Alzheimer's disease (ALZ) or amyotrophic lateral sclerosis (ALS), has aroused new interest in the field [11,12].

My work as a postdoctoral researcher in the laboratory of Dr. Schon at Columbia University was one of the first to link defects in MAM regulation and ER-mitochondrial contacts in ALZ [13-15]. Continuing my laboratory's line of research, my objective is to focus on the cause and consequences of MAM regulation defects, as well as the impact of lipid alterations on neuronal and inflammatory function in the context of neurodegenerative diseases such as ALZ and ALS.

1. Pera, M., et al., Increased localization of APP-C99 in mitochondria-associated ER membranes causes mitochondrial dysfunction in Alzheimer disease. EMBO J, 2017. 36(22): p. 3356-3371.
2. Montesinos, J., et al., The Alzheimer's disease-associated C99 fragment of APP regulates cellular cholesterol trafficking. EMBO J, 2020: p. e103791.
3. Scorrano, L., et al., Coming together to define membrane contact sites. Nat Com., 2019. 10(1): p. 1287.
4. Marquer, C., et al., Increasing membrane cholesterol of neurons in culture recapitulates Alzheimer's disease early phenotypes. Mol Neurodegener, 2014. 9: p. 60.
5. Herrera-Cruz, M.S. and T. Simmen, Over Six Decades of Discovery and Characterization of the Architecture at Mitochondria-Associated Membranes (MAMs). Adv Exp Med Biol, 2017. 997: p13-31.
6. Herrera-Cruz, M.S. and T. Simmen, Of yeast, mice and men: MAMs come in two flavors. Biol Direct, 2017. 12(1): p. 3.
7. Raturi, A. and T. Simmen, Where the endoplasmic reticulum and the mitochondrion tie the knot: the mitochondria-associated membrane (MAM). Biochim Biophys Acta, 2013. 1833(1): p. 213-24.
8. Rieusset, J., Mitochondria-associated membranes (MAMs): An emerging platform connecting energy and immune sensing to metabolic flexibility. Biochem Biophys Res Commun, 2018. 500(1): p. 35-44.
9. Hung, V., et al., Proteomic mapping of cytosol-facing outer mitochondrial and ER membranes in living human cells by proximity biotinylation. Elife, 2017. 6.
10. Xia, M., et al., Communication between mitochondria and other organelles: a brand-new perspective on mitochondria in cancer. Cell Biosci, 2019. 9: p. 27.
11. Area-Gomez, E. and E.A. Schon, Mitochondria-associated ER membranes and Alzheimer disease. Curr Opin Genet Dev, 2016. 38: p. 90-96.
12. Watanabe, S., et al., Mitochondria-associated membrane collapse is a common pathomechanism in SIGMAR1- and SOD1-linked ALS. EMBO Mol Med, 2016. 8(12): p. 1421-1437.
13. Area-Gomez, E., et al., Presenilins are enriched in endoplasmic reticulum membranes associated with mitochondria. Am J Pathol, 2009. 175(5): p. 1810-6.
14. Area-Gomez, E., et al., Upregulated function of mitochondria-associated ER membranes in Alzheimer disease. EMBO J, 2012. 31(21): p. 4106-23.
15. Schon, E.A. and E. Area-Gomez, Is Alzheimer's disease a disorder of mitochondria-associated membranes? J Alzheimers Dis, 2010. 20 Suppl 2: p. S281-92.