Abstract
Mitochondria-associated ER membranes (MAMs) are crucial for lipid transport and synthesis, calcium exchange, and mitochondrial functions, and they also act as signaling platforms. These contact sites also play a critical role in the decision between autophagy and apoptosis with far reaching implications for cell fate. Vascular smooth muscle cell (VSMC) apoptosis accelerates atherogenesis and the progression of advanced lesions, leading to atherosclerotic plaque vulnerability and medial degeneration. Though the successful autophagy of damaged mitochondria promotes VSMC survival against pro-apoptotic atherogenic stressors, it is unknown whether MAMs are involved in VSMC mitophagy processes. Here, we investigated the role of the multifunctional MAM protein phosphofurin acidic cluster sorting protein 2 (PACS-2) in regulating VSMC survival following a challenge by atherogenic lipids. Using high-resolution confocal microscopy and proximity ligation assays, we found an increase in MAM contacts as in PACS-2-associated MAMs upon stimulation with atherogenic lipids. Correspondingly, the disruption of MAM contacts by PACS-2 knockdown impaired mitophagosome formation and mitophagy, thus potentiating VSMC apoptosis. In conclusion, our data shed new light on the significance of the MAM modulatory protein PACS-2 in vascular cell physiopathology and suggest MAMs may be a new target to modulate VSMC fate and favor atherosclerotic plaque stability.
Highlights
The close membrane appositions between the mitochondrion and the endoplasmic reticulum (ER)form 10–50 nm wide contact sites commonly referred as mitochondria-associated ER membranes (MAMs) or mitochondria-ER contacts (MERCs) [1]
The colocalization area between mitochondria labelled with the translocase of outer membrane 20 (Tom20) and the ER marker KDEL was measured by confocal microscopy and showed a two-fold significant increase compared to the baseline condition (Figure 1a,b)
The calculation of the Pearson’s correlation coefficient (0.28 versus 0.63) confirmed that there is a significant association between mitochondria and the ER in oxidized low-density lipoproteins (LDL)-stimulated human VSMCs (hVSMCs) compared to baseline conditions (Figure 1e)
Summary
Form 10–50 nm wide contact sites commonly referred as mitochondria-associated ER membranes (MAMs) or mitochondria-ER contacts (MERCs) [1]. Such contact sites support the inter-organelle communication involved in the detection of extracellular inputs and stressful situations. The involvement of MAMs in the critical balance between cell survival and death has been recently suggested, because these contact sites play a vital role in modulating the decision between autophagy and apoptosis. The anti-apoptotic protein Bcl-2 binds to the autophagy protein
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