Mitochondria-endoplasmic reticulum contact sites in hepatocytic senescence

Abstract

Inter-organelle communication via membrane contact sites (MCSs) is essential for the efficient functioning of eukaryotic cells, facilitating coordination among approximately 20 distinct organelles, each with unique metabolic profiles. Among these interactions, mitochondria-endoplasmic reticulum (ER) contacts (MERCs) are particularly significant, encompassing about 5% of the mitochondrial surface. Key proteins involved in MERCs include inositol 1,4,5-trisphosphate receptor (IP3R), voltage-dependent anion channel (VDAC), glucose-regulated protein 75 (GRP75), Sigma1 receptor (Sig-1R), vesicle-associated membrane protein (VAMP)-associated protein B (VAPB), protein deglycase DJ-1, and protein tyrosine phosphatase interacting protein 51 (PTPIP51), with new proteins continually being identified for their roles in these structures. At these contact sites, metabolic exchanges involve calcium (Ca²⁺), lipids, reactive oxygen species (ROS), and proteins. MERCs enable efficient molecular exchanges through temporary bridges mainly formed by the ER, the organelle with the largest surface area. These contacts are crucial for maintaining mitochondrial dynamics, which is essential for cellular homeostasis, and they are notably impacted in pathological states such as metabolic dysfunction-associated steatotic liver disease (MASLD), alcohol-related liver diseases (ALD), and viral hepatitis. Dysfunctional MERCs can lead to mitochondrial fragmentation, increased ROS production, impaired autophagy, and disrupted protein trafficking, thereby exacerbating senescence and cellular aging. Senescence is a cell fate initiated by stress, characterized by stable cell-cycle arrest and a hypersecretory state, and is an underlying cause of aging and many chronic conditions, including liver diseases. The hallmarks of senescence-such as macromolecular damage, cell cycle withdrawal, deregulated metabolism, and a secretory phenotype-are well established. However, recent studies have demonstrated that senescence is a heterogeneous process, with molecular markers varying according to the stressors that induce it. This review focuses on the functional aspects of MERCs in hepatic senescence and their impact on liver diseases, and explores the potential of targeting MERCs to address hepatocytic senescence.

Keywords: Calcium; Contact sites; ER; Hepatocyte; MERCs; Mitochondria; Senescence.

Fig. 1

Inter-organelle communication via membrane contacts sites: A A schematic illustration depicting key inter-organelle tethering within a hepatocyte, with the bidirectional red arrow indicating inter-organellar interactions. B The proportion of cellular volume occupied by each organelle in a typical hepatocyte as described by Alberts et al. [181]. Each circle represents 1%, and the colors are assigned arbitrarily to improve visualization. C The number of contacts among various organelles per cell (fibroblast), as reported by Valm et al. [6]. Created with BioRender.com

Fig. 2

Functional roles of mitochondria–endoplasmic reticulum contact sites (MERCs) in metabolic exchange and signaling. MERCs act as critical hubs for inter-organelle communication, coordinating multiple cellular processes: A Calcium transfer: MERCs facilitate efficient Ca²⁺ shuttling from the ER to mitochondria through protein complexes involving IP3R–GRP75–VDAC1, MCU, and associated regulatory proteins (e.g., MFN2, PDZD8, DJ-1, and BCL2). This Ca^2⁺ transfer supports mitochondrial metabolism, including the tricarboxylic acid (TCA) cycle, but excessive Ca²⁺ can promote mitochondrial stress. B Lipid exchange: MERCs mediate the transfer of phospholipids (phosphatidylserine [PS], phosphatidylethanolamine [PE], phosphatidylcholine [PC]) via enzymes such as PSD1p and PEMT2, as well as cholesterol and citrate transport involving proteins such as ATAD3A, caveolin-1 (Cav-1), and SGIP1. These exchanges contribute to lipid droplet formation and de novo lipogenesis (DNL). C Protein trafficking: MERCs participate in mitochondrial protein import through ER-associated translocation machinery (e.g., Sec61 complex and SPC) and mitochondrial import systems (TOM, TIM, and Oxa1), as well as ERMES complex proteins (Mdm10, Mdm12, Mdm34, and Gem1) that coordinate ER–mitochondria tethering. D ROS signaling: MERCs are sites of reactive oxygen species (ROS) generation and signaling, linking mitochondrial electron transport chain (ETC) activity to ER stress pathways via components such as CYP450 enzymes (CYPB5R3 and CYPB5R) and NOX4. ROS accumulation activates ER stress sensors (IRE1 and PERK), influencing cell fate and stress responses. Created with BioRender.com

Fig. 3

MERC remodeling, and cellular senescence. A Pro-senescent stressors, such as oxidative stress, lipid overload, inflammation, and viral infection, trigger initial reductions in mitochondria–endoplasmic reticulum contact sites (MERCs), followed by a compensatory increase during the establishment of senescence. Increased MERCs disrupt inter-organelle communication, contributing to decreased mitochondrial fission and fusion, impaired autophagy, and sustained mitochondrial dysfunction. These MERC-driven processes contribute to hepatocellular senescence and the development of the senescence-associated secretory phenotype (SASP), which further propagates liver injury and fibrosis. Dashed arrows indicate proposed mechanistic links; question marks denote relationships requiring further clarification. B Intracellular molecular characteristics of a typical senescent cell: Senescence involves several key changes. Morphologically, senescent cells exhibit increased size and granularity. Within the nucleus, there is a loss of nuclear membrane integrity, telomere shortening, DNA damage, and the formation of senescence-associated heterochromatin foci. In peroxisomes, changes include reduced catalase activity, increased reactive oxygen species (ROS), an increase in number, and impaired communication with mitochondria. Mitochondrial changes include increased mass, reduced bioenergetic efficiency, heightened ROS production, and decreased membrane integrity. In lysosomes, there is an increase in mass, elevated SA-β-galactosidase activity, and the accumulation of lipofuscin. Created with BioRender.com

Fig. 4

Impact of MERCs on cellular processes in liver diseases. A A high number of mitochondrial–ER contact sites (MERCs) is associated with enhanced Ca²⁺ signaling, insulin signaling, lipid metabolism, energy metabolism, and the regulation of apoptosis. Conversely, a low number of MERCs is linked to increased autophagy, an enhanced ER stress response, and various cytosolic processes. MERC-mediated mechanisms linking hepatocellular senescence to chronic liver disease progression in MASLD, ALD, and viral hepatitis. B In metabolic dysfunction-associated steatotic liver disease (MASLD), metabolic stress induces disruption of mitochondria–endoplasmic reticulum contact sites (MERCs), leading to mitochondrial dysfunction, ER stress, and activation of senescence pathways. The resulting senescence-associated secretory phenotype (SASP) drives inflammation and disease progression. C In alcohol-related liver disease (ALD), chronic alcohol exposure promotes excessive MERCs formation via the PDK4–GRP75 pathway, causing mitochondrial Ca²⁺ overload, oxidative stress, and activation of pro-inflammatory signaling, culminating in hepatocellular senescence and ALD progression. D In viral hepatitis, chronic HBV or HCV infection triggers host stress responses and MAPK pathway activation, disrupting MERCs and impairing mitochondrial function. These events facilitate the establishment of hepatocellular senescence and contribute to ongoing liver injury and disease progression. Created with BioRender.com