Critical Hubs of Renal Ischemia-Reperfusion Injury: Endoplasmic Reticulum-Mitochondria Tethering Complexes

Renal ischemia-reperfusion (I/R) injury is a severe complication that occurs after organ transplantation, heart surgery, and other major operations. It is the most common cause of acute kidney injury (AKI), with a mortality rate as high as 50% in intensive care units. During surgery, the blood supply to the kidney is temporarily limited, and when perfusion is restored, reoxygenation causes inevitable damage to the kidney. The recognized mechanisms of renal I/R injury include mitochondrial dysfunction, endoplasmic reticulum (ER) stress, apoptosis, necrosis, oxidative stress, and inflammation. Among these, mitochondrial dysfunction and ER stress play particularly critical roles. Increasing evidence shows that the functions of the ER and mitochondria are highly interconnected both physiologically and pathologically. Effective communication and cooperation between these organelles depend on direct membrane contact, which is facilitated by specialized membrane microdomains known as ER-mitochondria tethering complexes.

Structure and Components of ER-Mitochondria Tethering Complexes

The physical interaction between the ER and mitochondria has been extensively studied using electron microscopy. The minimum distance between the outer mitochondrial membrane (OMM) and the ER is approximately 10 nm for the smooth ER and 25 nm for the rough ER. In yeast, a protein complex called the ER-mitochondria encounter structure (ERMES) has been identified, but no direct mammalian orthologs have been found. Instead, several protein complexes have been proposed as ER-mitochondria tethers in mammals. These tethering complexes are composed of various proteins that physically connect the ER to mitochondria, playing essential roles in cellular processes such as calcium homeostasis, lipid metabolism, apoptosis, and mitochondrial dynamics.

Key components of these tethering complexes include:

Inositol 1,4,5-Trisphosphate Receptor (IP3R): Located on the ER membrane, IP3R is a calcium channel that interacts with the voltage-dependent anion channel (VDAC) and the mitochondrial chaperone glucose regulatory protein 75 (GRP75) to form a ternary complex, facilitating calcium transfer from the ER to mitochondria.
Mitofusin-2 (MFN2): MFN2 is located on both the ER and mitochondrial membranes and is involved in mitochondrial fusion and fission. It also interacts with the ER transmembrane protein PERK (protein kinase R-like endoplasmic reticulum kinase) to regulate ER-mitochondrial communication.
Phosphofurin Acidic Cluster Sorting Protein 2 (PACS-2): PACS-2 is a multifunctional sorting protein that regulates ER-mitochondrial communication and is involved in apoptosis under stress conditions.
Vesicle-Associated Membrane Protein-Related Protein B (VAPB): VAPB interacts with protein tyrosine phosphatase-interacting protein 51 (PTPIP51) to tether the ER to mitochondria and regulate calcium homeostasis.
FUN14 Domain-Containing Protein 1 (FUNDC1): FUNDC1 is a mitochondrial protein that interacts with IP3R to regulate mitochondrial calcium homeostasis and is involved in hypoxia-induced mitophagy.
Dynamin-Related Protein 1 (DRP1): DRP1 is a key regulator of mitochondrial fission and is recruited to sites where the ER and mitochondria are in contact.

These proteins and their interactions form the structural basis of ER-mitochondria tethering complexes, which are essential for maintaining the functional integrity of both organelles.

Mechanisms of Renal I/R Injury Involving ER-Mitochondria Tethering Complexes

Mitophagy

Mitophagy is a selective form of autophagy that specifically targets damaged or excess mitochondria for degradation. It plays a crucial role in maintaining mitochondrial quality control and is implicated in various diseases, including renal I/R injury. ER-mitochondria tethering complexes serve as platforms for mitophagy, as autophagosome membranes are thought to originate from the ER. Imaging studies have shown that autophagosomes form at ER-mitochondria contact sites.

The process of mitophagy can be divided into ubiquitin (Ub)-dependent and Ub-independent mechanisms. In the Ub-dependent pathway, the stabilization of PTEN-induced kinase 1 (PINK1) on the outer mitochondrial membrane (OMM) recruits the E3-Ub ligase parkin, which ubiquitinates OMM proteins, marking them for degradation. MFN2 has been shown to interact with PINK1 and parkin, although its exact role in parkin recruitment remains controversial. In Ub-independent mitophagy, receptors such as BCL2 interacting protein 3 (BNIP3), BNIP3-like (NIX), and FUNDC1 directly bind to the autophagy protein LC3 to initiate mitophagy.

In renal I/R injury, mitophagy plays a protective role by removing damaged mitochondria and reducing oxidative stress. Studies have shown that deficiencies in PINK1 or parkin exacerbate ischemic AKI, while activation of BNIP3-mediated mitophagy protects against renal I/R injury. FUNDC1, which is enriched on mitochondrial-associated membranes (MAMs) under hypoxic conditions, also plays a critical role in hypoxia-induced mitophagy and mitochondrial fission.

Mitochondrial Fission and Fusion

Mitochondrial dynamics, including fission and fusion, are essential for maintaining mitochondrial function and quality control. During renal I/R injury, mitochondrial fragmentation is observed, which is mediated by the fission protein DRP1. DRP1 is recruited to sites where the ER and mitochondria are in contact, and its activation leads to mitochondrial fission. Inhibition of DRP1 has been shown to reduce mitochondrial fragmentation and protect against renal I/R injury.

Mitochondrial fusion, on the other hand, is regulated by MFN1, MFN2, and optic atrophy 1 (OPA1). MFN2, in particular, is involved in tethering the ER to mitochondria and promoting mitochondrial fusion. The balance between fission and fusion is critical for maintaining mitochondrial function, and disruptions in this balance can lead to mitochondrial dysfunction and cell death.

Apoptosis and Necrosis

Apoptosis and necrosis are two major forms of cell death implicated in renal I/R injury. ER-mitochondria tethering complexes play a significant role in regulating these processes. For example, the interaction between Fis1 (a mitochondrial fission protein) and Bap31 (an ER protein) forms a platform for apoptosis induction. Under stress conditions, Fis1 recruits procaspase-8, which cleaves Bap31 and triggers ER calcium release, leading to cytochrome c release and apoptosis.

Necrosis, particularly necroptosis, is another form of cell death that occurs during renal I/R injury. Receptor-interacting protein kinase 3 (RIPK3) has been shown to mediate necroptosis, and its ablation protects against renal I/R injury. The opening of the mitochondrial permeability transition pore (mPTP), which is regulated by components of the tethering complexes such as VDAC, is a key event in necrosis.

ER Stress

ER stress is a critical mechanism of renal I/R injury. When misfolded proteins accumulate in the ER, the unfolded protein response (UPR) is activated to restore normal cell function. The UPR involves three main pathways: PERK, inositol-requiring enzyme 1 (IRE1), and activating transcription factor 6 (ATF6). ER-mitochondria tethering complexes play a crucial role in transmitting stress signals from the ER to mitochondria.

PERK, for example, interacts with MFN2 to regulate ER-mitochondrial communication. Under stress conditions, PERK activates the PERK/eukaryotic initiation factor 2α (eIF2α)/ATF4 pathway, which regulates autophagy and apoptosis. Inhibition of ER stress has been shown to reduce renal I/R injury, highlighting the importance of ER-mitochondria tethering complexes in this process.

Mitochondrial Material Transport and Lipid Metabolism

Mitochondrial biogenesis and lipid metabolism are essential for maintaining cellular energy homeostasis during renal I/R injury. Mitochondria rely on the ER for the synthesis and transport of lipids and proteins. ER-mitochondria tethering complexes facilitate the transfer of lipids such as phosphatidylserine (PS), phosphatidylethanolamine (PE), and cardiolipin (CL) from the ER to mitochondria.

Lipid synthesis enzymes, including phosphatidylserine synthase and phosphatidylethanolamine N-methyltransferase 2, are localized at ER-mitochondria contact sites. Disruptions in lipid metabolism can lead to mitochondrial dysfunction and cell death, underscoring the importance of ER-mitochondria tethering complexes in maintaining lipid homeostasis.

Conclusion and Future Perspectives

ER-mitochondria tethering complexes are critical hubs in the pathophysiology of renal I/R injury. They play essential roles in mitophagy, mitochondrial dynamics, apoptosis, necrosis, ER stress, and lipid metabolism. Understanding the structure and function of these complexes provides valuable insights into the mechanisms of renal I/R injury and offers potential therapeutic targets.

Future research should focus on elucidating the specific interactions between the components of ER-mitochondria tethering complexes and their roles in renal I/R injury. Additionally, the development of drugs that target these complexes could provide new strategies for preventing and treating renal I/R injury. As our understanding of these complexes continues to grow, so too will our ability to mitigate the devastating effects of renal I/R injury.

doi.org/10.1097/CM9.0000000000001091

Was this helpful?

0 / 0