Journal of Nephrology

Mitochondrial Dyssfunction in Renal Ischemia-Reperfusion Injury: Mechanisms and Therapeutic Implications for Kidney Transplantation

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Abstract

Ischemia-Reperfusion Injury (IRI) in kidney Transplantation (KTx) is intricately associated with acute rejection, Delayed Graft   Function (DGF), and allograft failure. Substantial evidence underscores a significant correlation between mitochondrial dysfunction   and the pathophysiology of IRI. Mitochondria serve as essential regulators of cellular energy metabolism, redox homeostasis,   and apoptosis, thereby contributing to IRI through a myriad of mechanisms. This review summarizes the pathological role of   mitochondria in renal IRI and critically evaluates recent advancements in mitochondria-targeted therapies designed to ameliorate   transplant-related IRI.

Keywords

Mitochondrial dysfunction; Ischemia reperfusion injury; Kidney transplantation

INTRODUCTION

Ischemia-Reperfusion Injury (IRI) is an unavoidable consequence of Kidney Transplantation (KTx). The transplantation process entails periods of cold and warm ischemia followed by reperfusion, which can severely compromise the graft [1,2]. During this cascade, the activation of immune cells leads to the release of inflammatory mediators and the generation of oxidative stress. This cascade induces aseptic inflammation and inflicts damage upon endothelial and renal tubular epithelial cells, thereby elevating the risk of Acute Kidney Injury (AKI), Delayed Graft Function (DGF), and potential allograft failure [3,4]. Therefore, enhancing our understanding of the molecular and biological alterations associated with IRI in KTx is imperative.

Mitochondria, abundant in the kidney, are essential organelles that fulfill multiple roles within cells. They serve as primary energy generators, producing Adenosine Triphosphate (ATP) through oxidative phosphorylation [5]. Additionally, mitochondria are vital for regulating cellular metabolism, maintaining calcium ion balance, generating Reactive Oxygen Species (ROS), facilitating signal transduction, and governing cell cycle progression and apoptosis [6-8]. Thus, normal mitochondrial activity is essential for maintaining cellular homeostasis, while mitochondrial dysfunction is associated with the onset and progression of various diseases. Research on mitochondria may offer deeper insights into the mechanisms underlying KTx-associated IRI (KTx-IRI). Moreover, restoring healthy mitochondrial function and mass is vital for the recovery of renal function.

This review examines mitochondrial mechanisms in KTx-IRI and explores mitochondrial preservation strategies. Synthesizing preclinical and clinical evidence, we highlight translational potential of mitochondria-targeted therapies for KTx and identify research challenges.

Mitochondrial pathogenesis in renal IRI

Mitochondrial dysfunction is a central driver of renal IRI, contributing significantly to cellular damage through multiple interconnected mechanisms. The pathogenesis primarily involves disruptions in energy metabolism, oxidative stress, calcium homeostasis, and activation of cell death pathways, ultimately leading to AKI and impaired graft function in KTx.

Energy metabolism collapse

During ischemia, oxygen deprivation halts oxidative phosphorylation, leading to severe ATP depletion [9]. Proximal tubular cells, which are highly dependent on mitochondrial ATP for active solute reabsorption, are particularly vulnerable. The loss of ATP impairs ion pump function (Na⁺/K⁺-ATPase), resulting in cellular edema, loss of polarity, and disruption of tight junctions [10]. Upon reperfusion, despite oxygen restoration, mitochondrial damage persists due to Electron Transport Chain (ETC) dysfunction, further delaying ATP recovery and exacerbating cellular injury.

Oxidative stress and ROS burst

Reperfusion triggers an explosive production of ROS, primarily from compromised mitochondrial ETC complexes [11]. Mitochondria-derived ROS (mtROS) cause oxidative damage to lipids, proteins, and DNA, and activate inflammatory pathways such as NLRP3 inflammasome and NF-κB signaling [12-14]. This amplifies sterile inflammation and recruits immune cells, further damaging renal tissues.

Calcium overload and mPTP opening

Ischemia disrupts cellular Ca²⁺ homeostasis due to ATPase failure, leading to calcium overload within mitochondria. Elevated matrix Ca²⁺, coupled with oxidative stress and ATP depletion, promotes the opening of the mitochondrial Permeability Transition Pore (mPTP) [15,16]. Persistent mPTP opening causes Mitochondrial swelling, Outer Membrane Permeabilization (MOMP), and release of pro-apoptotic factors into the cytosol, activating caspase-dependent apoptosis and necroptosis [17,18].

Dysregulation of mitochondrial dynamics

Renal IRI disrupts mitochondrial homeostasis by perturbing the critical balance between fission and fusion. Excessive fission, driven by Drp1 activation, results in pathological mitochondrial fragmentation. While facilitating the segregation of damaged organelles, this process promotes apoptosis if clearance is impaired [19,20]. Conversely, impaired fusion, characterized by downregulation of Mfn1, Mfn2, and Opa1, reduces mitochondrial connectivity and compromises metabolic cooperation and genomic stability, thereby heightening cellular susceptibility to stress [21].

Impaired mitophagy

Dysfunctional mitochondria are normally removed via mitophagy. In IRI, key mitophagy pathways (PINK1/Parkin, BNIP3, FUNDC1) are often impaired or overwhelmed [22-24]. Defective mitophagy results in the accumulation of damaged mitochondria, perpetuating ROS production, inflammation, and cell death. Conversely, excessive mitophagy may also deplete functional mitochondria, exacerbating energy crisis.

Inflammatory activation

mtROS and released mitochondrial DNA (mtDNA) act as Damage-Associated Molecular Patterns (DAMPs), activating Toll-like receptors or nucleotide-binding oligomerization domain-containing protein (NOD)-like receptors, leading inflammation, characterized by cytokine release, endothelial activation, and immune cell infiltration, further propagating tubular injury and microvascular dysfunction [25-27].

Interorganellar crosstalk dysfunction

The endoplasmic reticulum-mitochondria interface at Mitochondrial-Associated Membranes (MAMs) is disrupted in IRI [28]. This impairs calcium signaling, lipid transfer, and apoptotic regulation. MAMs also serve as platforms for autophagosome formation, and their dysfunction contributes to impaired mitophagy. FUNDC1 interaction with ER-resident proteins at MAMs helps coordinate mitochondrial fission in response to hypoxia [29].

Transition to chronic pathology

Persistent mitochondrial dysfunction post-AKI promotes metabolic reprogramming (glycolytic shift) and fibrotic signaling (TGF-β, α-SMA), driving AKI-to-Chronic Kidney Disease (CKD) transition [10,30]. Mitochondrial defects in various renal cells contribute to capillary rarefaction, glomerulosclerosis, and interstitial fibrosis. Transmission electron microscopy studies show persistent mitochondrial abnormalities in endothelial cells, podocytes, and tubular cells long after initial injury [31].

Mitochondrial damage in kidney transplantation

Mitochondrial dysfunction is a central pathogenic mechanism in renal IRI, an inevitable component of KTx that compromises mitochondrial integrity and function [1]. Growing evidence confirms its critical role in transplant-related injury.

During donor procurement, warm ischemia rapidly depletes ATP, collapsing the mitochondrial membrane potential and arresting oxidative phosphorylation [1]. Subsequent static cold storage exacerbates ionic imbalance and induces mitochondrial swelling and cristae disruption due to substrate deficiency [2]. Reperfusion, however, causes the most profound damage. Abrupt reoxygenation of impaired mitochondria triggers explosive mtROS production from defective ETC, leading to extensive oxidative damage to lipids, proteins, and mtDNA [4]. This is frequently accompanied by pathological mPTP opening, cytochrome c release, and activation of cell death pathways [3]. Proximal tubular cells, with high energy demands, are particularly vulnerable. Mitochondria dysfunction was an important non immune factor involved in chronic allograft injury and directly correlates with key transplantation outcomes [32].

In our previous analysis, we identified 16 Differentially Expressed Mitochondrial Genes (DE-MGs) in KTx-IRI patients versus controls. We further identified two molecular clusters: C1, associated with inflammatory/immune activation and higher incidence of DGF, and C2, characterized by active metabolic pathways and lower DGF rates [33].

Mitochondria-targeted transplantation interventions in kidney

Mounting evidence underscores the central role of mitochondrial dysfunction in the pathogenesis of renal IRI, making it a promising therapeutic target to improve outcomes in KTx. Current strategies focus on preserving mitochondrial integrity, enhancing quality control, and restoring bioenergetic efficiency through pharmacological agents, conditioning techniques, and advanced organ preservation technologies (Table 1).

Table 1: Mitochondria-targeted interventions in kidney transplantation..

Several compounds specifically designed to target mitochondrial pathways show significant potential. MitoQ, a mitochondria targeted antioxidant, which could effectively reduce mtROS and oxidative damage, demonstrating protective effects in experimental models of renal IRI [34]. SS-31, a cell-permeable peptide that binds to cardiolipin in the inner mitochondrial membrane. It stabilizes mitochondrial cristae, improves ETC efficiency, and inhibits mPTP opening, thereby preserving ATP synthesis and reducing apoptosis [35]. Clinical trials have shown improved mitochondrial function in various ischemic conditions. Furthermore, there are others pharmacological agents designed to target mitochondrial energy metabolism, mitophagy, and mitochondrial fusion and fission, thus mitigating renal IRI in KTx [36].

Beyond pharmacological strategies, non-pharmacological approaches targeting mitochondrial dysfunction also show promise in attenuating renal IRI during KTx. Remote Ischemic Preconditioning (RIPC) applies brief ischemia-reperfusion cycles to a remote tissue, triggering systemic protection through humoral and neural pathways that enhance renal mitochondrial antioxidant defense, stabilize ETC activity, and inhibit mPTP opening, thus improving ischemic resilience [37]. Machine perfusion technology, especially Hypothermic (HOPE) and Normothermic (NMP) perfusion, outperforms static cold storage by continuous oxygenation and substrate delivery, mitigating ATP depletion and mitochondrial degradation [38]. These methods exemplify the translation of mitochondrial protective mechanisms into clinical strategies for enhancing graft viability.

DISCUSSION

The findings synthesized in this review underscore mitochondrial dysfunction as a central pathogenic driver in renal IRI and its critical implications for KTx outcomes. Our analysis reaffirms that mitochondrial impairment-characterized by bioenergetic failure, oxidative stress, calcium dysregulation, aberrant dynamics, and defective quality control-serves as a key mediator of tubular injury, inflammation, and cell death post-IRI. Notably, the vulnerability of proximal tubular cells, owing to their high metabolic demands, positions mitochondria as both a trigger and amplifier of damage during the stages of graft procurement, preservation, and reperfusion.

Several salient points emerge from the accumulated evidence. First, the persistence of mitochondrial damage beyond the acute phase, often manifesting as metabolic reprogramming and maladaptive repair, underscores its role in the transition from AKI to CKD. This is of particular relevance in transplantation, where long-term allograft survival remains a paramount concern. Second, the identification of distinct molecular clusters associated with mitochondrial gene expression profiles offers a potential stratifying tool for predicting graft function and personalizing therapeutic interventions.

While pharmacological agents such as MitoQ, and SS-31, show promise in preclinical models, their translation into clinical practice requires further validation through robust randomized trials. Moreover, non-pharmacological strategies like RIPC and machine perfusion represent innovative approaches to mitigate mitochondrial injury ex vivo and in situ. Particularly, machine perfusion systems-especially when augmented with mitochondrial protectants-provide a viable platform for graft reconditioning, providing oxygenation, substrate support, and targeted drug delivery.

However, challenges remain. The heterogeneity of donor conditions, variations in ischemia times, and recipient factors complicate standardized mitochondrial therapeutic protocols. Furthermore, while biomarkers such as cell-free mtDNA, offer non-invasive means of assessing mitochondrial injury, their clinical utility and predictive value warrant larger prospective studies.

CONCLUSION

Mitochondrial dysfunction is an indispensable contributor to the pathophysiology of renal IRI and a determinant of outcomes in KTx. The mechanisms underlying mitochondrial damage-including energy collapse, ROS overproduction, mPTP opening, dynamic imbalance, and impaired mitophagy-provide a repertoire of targetable pathways for therapeutic intervention. In summary, a mitochondria-centric approach offers a promising framework for improving graft quality, reducing DGF, and enhancing long-term transplant survival. By elucidating and targeting the metabolic core of IRI, we move closer to achieving precision medicine in KTx.

ACKNOWLEDGEMENTS

The authors thank all the participants of the study.

FINANCIAL SUPPORT AND SPONSORSHIP

This work was supported by Wannan Medical College Young and Middle-aged Research Fund (YR202440, Danni Hu; YR202503, Zheng Wang).

CONFLICT OF INTEREST

The authors state that they do not have any conflicts of interest.

AUTHOR CONTRIBUTIONS

This article was conceptualized by ZW. DH collated the literature for review. DH drafted the manuscript and was responsible for revising it.

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Received: 26-Aug-2025 Accepted Date: 01-Sep-2025 Published: 10-Oct-2025

Citation: Hu D, Wang Z. (2025) Mitochondrial Dysfunction in Renal Ischemia-Reperfusion Injury: Mechanisms and Therapeutic Implications for Kidney Transplantation. J Nephrol.1: 002.

Copyright: © 2025 Hu D, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.