Interaction of Mitochondria with the Endoplasmic Reticulum and Plasma Membrane in Calcium Homeostasis, Lipid Trafficking and Mitochondrial Structure

Abstract

Studying organelles in isolation has been proven to be indispensable for deciphering the underlying mechanisms of molecular cell biology. However, observing organelles in intact cells with the use of microscopic techniques reveals a new set of different junctions and contact sites between them that contribute to the control and regulation of various cellular processes, such as calcium and lipid exchange or structural reorganization of the mitochondrial network. In recent years, many studies focused their attention on the structure and function of contacts between mitochondria and other organelles. From these studies, findings emerged showing that these contacts are involved in various processes, such as lipid synthesis and trafficking, modulation of mitochondrial morphology, endoplasmic reticulum (ER) stress, apoptosis, autophagy, inflammation and Ca 2 + handling. In this review, we focused on the physical interactions of mitochondria with the endoplasmic reticulum and plasma membrane and summarized present knowledge regarding the role of mitochondria-associated membranes in calcium homeostasis and lipid metabolism.

Keywords: endoplasmic reticulum; lipid metabolism and trafficking; mitochondria; mitochondria-associated membranes (MAM); plasma membrane; plasma membrane-associated membranes (PAM).

Figure 1

Image of plasma membrane (PM) (green) and mitochondria (red) in HeLa cells. Cells were transfected with pCAG-mGFP (for staining the PM) and mito-mNeptune (for staining the mitochondria). (A) Image of the endoplasmic reticulum (ER) (green) and mitochondria (red) in U2OS cells. The cells were transfected with pAc-GFPC1-Sec61-$\beta$ plasmid (for staining the ER) and mito-mNeptune (for staining the mitochondria); (B) An example of a fission event is shown in the enlarged inset region (four selected images from the time series acquired with a 2-s time step). The fission event takes place between the time points of 10 and 12 s. The localization of the fission event is indicated with a yellow arrow in each channel ((C) overlay, (D) ER, (E) mitochondria). The ER structure is clearly visible at the fission site. Imaging was performed using Zeiss spinning disc microscope. The white scale bar in (A) and in (B) corresponds to 10 $\mathsf{\mu }$m; the green scale bar in (C) corresponds to 2 $\mathsf{\mu }$m. Experiments were performed with similar procedures as reported elsewhere [18].

Figure 2

Proteins involved in Ca${}^{2+}$ homeostasis at MAM and PAM fractions. Bak, Bcl-2 antagonist/killer; Bax, Bcl-2 associated X protein; Bcl-2, B-cell CLL/lymphoma 2; BIP1, or GRP78, glucose regulated protein 78; cyt. c, cytochrome c; ER, endoplasmic reticulum; GRP75, glucose regulated protein 75; HK2, hexokinase 2; IP3R, inositol 1,4,5 trisphosphate receptor; MAM, mitochondria associated membranes; Mcl-1, myeloid cell leukemia sequence 1; MCU, mitochondrial calcium uniporter; mPTP, mitochondrial permeability transition pore; Orai1, ORAI Calcium Release-Activated Calcium Modulator 1; PAM, plasma membrane associated membranes; PM, plasma membrane; PML, promyelocytic leukemia protein; PTEN, phosphatase and tensin homolog deleted on chromosome 10; SERCA, sarco/endoplasmatic reticulum Ca${}^{2+}$ ATPase; Sig1R, Sigma 1 receptor; STIM1, Stromal interaction molecule 1; VDAC, voltage-dependent anion channel.

Figure 3

Lipid trafficking at the mitochondria-associated membranes. The ER-mitochondria interface fosters the transport of phospholipids, cholesterol (Chol) and ceramides (Cer). Particular lipid species exodus is integrated by a network of MAM residing enzymes (marked in red), including PSS1, PSS2, PSD, PEMT2, cytochrome P450, SMase, CerS and DES. Abbreviations: PA, phosphatidic acid; PS, phosphatidylserine; PE, phosphatidylethanolamine; PC, phosphatidylcholine; Preg, pregnolone.