Mitochondria-Targeted Therapies May Transform Acute Kidney Injury Treatment

Mitochondria-targeted therapies may play a key role in the transformation of acute kidney injury (AKI) treatment, according to authors of research findings published in Genes & Diseases. Despite its promise, the authors emphasized that there is a need for additional research to ensure efficacy across different models and to mitigate any potential adverse events (AEs).^1,2

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AKI is a condition in which kidneys lose their ability to filter waste products from the blood, resulting in fluid and waste buildup. It is most common in patients who are in the hospital. Although AKI can be reversed, if the disease is severe and untreated, it can be fatal. Symptoms often involve decreased urinary output, swelling from fluid retention, nausea, fatigue, and shortness of breath, and in some patients, they may not be present.³

Ongoing research has demonstrated that AKI appears to be both a cause and consequence of chronic kidney disease (CKD), in which AKI may progress to CKD, or severe CKD can result in kidney injury. Underlying CKD is recognized as a risk factor for AKI, as both decreased glomerular filtration rates and increased proteinuria—symptoms of CKD—have also been shown to be strongly associated with AKI. Additionally, patients who have AKI that requires dialysis are particularly vulnerable to worse long-term renal outcomes, including end-stage kidney disease, which is the most advanced stage of CKD.³

Because AKI continues to remain a significant global health challenge with high mortality rates and the potential for CKD progression, there is a significant need for intervention methods. One potential avenue of intervention the authors detailed is targeting mitochondrial biogenesis, a critical cellular process that promotes energy metabolism, stress resistance, and cell survival. Through mitochondrial biogenesis enhancement, there is potential to restore mitochondrial function, alleviate oxidative stress, and improve renal recovery in patients living with AKI.^1,2

The kidneys are highly dependent on robust mitochondrial function because of their substantial energy demands, explained the authors. During AKI, mitochondrial dysfunction leads to a decreased production of energy, heightened oxidative damage, and cell death, which further exacerbates kidney injury. Suppressing mitochondrial biogenesis would not only disrupt cellular energy balance but also impair the ability to respond to injurious stimuli, accelerating disease progression. Therefore, therapeutic strategies that could boost mitochondrial biogenesis would significantly mitigate AKI severity and enhance outcomes for patients.^1,2

Several factors regulate mitochondrial biogenesis, including PGC-1α, a transcriptional coactivator that stimulates the expression of genes involved in mitochondrial function. Activation of this improves ATP production, reduces reactive oxygen species, and supports cell survival during stress. Additionally, compounds like resveratrol—which activate PGC-1α through SIRT1-mediated deacetylation—have promise in promoting mitochondrial health. Further, small molecules like ZLN005 and pyrroloquinoline quinone can enhance mitochondrial biogenesis through pathways involving AMPK activation and CREB phosphorylation, respectively.^1,2

Despite its promise in AKI, mitochondrial biogenesis regulation is complex, and excessive activation may lead to protein misfolding, mitochondrial damage, and cellular toxicity. Therefore, achieving a balanced activation of mitochondrial biogenesis is crucial in the prevention of AEs. Translating such mitochondrial biogenesis insights into clinical practice is needed to overcome challenges related to drug specificity, targeted delivery, and patient variability. Personalized approaches that take the etiology and subtype of AKI and patient-specific factors (eg, comorbidities) into consideration are essential for optimizing treatment, according to the authors. Additionally, integrating multiomics data that can help identify biomarkers that predict treatment response can allow for more precise and effective therapies.^1,2

Mitochondria-targeted therapies hold great potential for improving AKI treatment. By addressing the underlying mitochondrial dysfunction, such strategies offer a pathway to enhance renal recovery, reduce disease progression, and improve patient survival. The authors wrote that future research should focus on the optimization of drug design, understanding mitochondrial biogenesis regulation, and conducting clinical trials to establish effective treatments for patients with AKI.^1,2

REFERENCES

1. Hao Y, Chen F, Ren X, Huang X, Zhou X. Harnessing mitochondrial biogenesis to combat acute kidney injury: Current insights and future directions. Genes Dis. 2025;12(6):101645. Published 2025 Apr 15. doi:10.1016/j.gendis.2025.101645

2. Compscript LTD. Unlocking the power of mitochondrial biogenesis to combat acute kidney injury. News release. August 15, 2025. Accessed August 28, 2025. https://www.eurekalert.org/news-releases/1094945

3. Hsu RK, Hsu CY. The Role of Acute Kidney Injury in Chronic Kidney Disease. Semin Nephrol. 2016;36(4):283-292. doi:10.1016/j.semnephrol.2016.05.005.