Mitochondria: The Crossroads of Complement Activation and Kidney Injury Progression

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

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Author Response

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Reviewer 2 Report

Comments and Suggestions for Authors

This proposed review “Mitochondria: the crossroads of kidney ischemia- reperfusion injury severity and progression” presents a timely and informative overview of the relationship between complement activation and mitochondrial dysfunction in kidney disease. The manuscript summarizes recent findings in the field and provides valuable insights into potential therapeutic targets. Overall, the review is well written, although several minor revisions may further strengthen the manuscript.

1. The review provides a comprehensive overview of the relationship between complement activation and mitochondrial dysfunction in kidney injury. However, the authors may consider expanding the limitations section by further discussing the predominance of preclinical evidence and the current lack of direct clinical validation of several proposed mechanisms.
2. The manuscript would benefit from a brief section outlining future research directions, particularly regarding the translation of complement-targeted therapies from experimental models to clinical practice in AKI and CKD.
3. In Section 4.2.3, the authors discuss studies reporting both mitochondrial fission and fusion following C5aR1 activation. A brief discussion addressing potential reasons for these apparently conflicting findings (e.g., cell type, experimental conditions, or disease context) would improve the clarity of the manuscript.

Author Response

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Reviewer 3 Report

Comments and Suggestions for Authors

The presented work is a review article dedicated to the role of mitochondrial dysfunction and the complement system (with a focus on the C5 component) in the pathogenesis of ischemic-reperfusion kidney damage, the transition of acute kidney damage to chronic kidney disease (and the terminal stage). The article is written in clear scientific language, well-structured, and contains relevant references (including works from 2024-2025). The volume and depth correspond to the format of a review.  The topic is highly relevant: AKI and CKD remain the leading causes of mortality and disability, and available therapeutic strategies are limited to dialysis and transplantation. The authors rightfully focus on two interrelated mechanisms: mitochondrial dysfunction and complement activation, which were previously often considered in isolation. The hypothesis that the terminal C5 protein is the central link between these processes has significant scientific and clinical implications (with already approved anti-C5 drugs). Thus, this article contributes to the formation of a new paradigm, which considers complement not only as an immune effector, but also as a regulator of cellular metabolism. 

The authors convincingly show that mitochondria and complement are not independent pathways, but form a single network (C5aR1 on the outer mitochondrial membrane, the effect of C5a on mitochondrial division/fusion, ROS production, and apoptosis). This is an important conceptual generalization. Despite its fundamental nature, the article constantly returns to therapeutic targets (C5, C5aR1) and existing drugs (eculizumab, ravulizumab, avacopril). The article discusses the problems of C5 genetic variants and incomplete response to therapy. Despite its high quality, the article has several weaknesses that should be addressed in the revision process: 

1.   In section 4.2.3, the authors mention conflicting data: Ishii & Rohrer report that C5a induces mitochondrial fusion, while other authors (Ye et al., Tsai et al.) report that it induces mitochondrial division. This is presented as "likely dependent on cell type," but without analyzing the possible reasons (different concentrations of C5a, the presence of co-factors, or the models used). A table or a more in-depth discussion should be added.
2. Lack of quantitative data and meta-analysis. For a review of this level, it would be useful to provide a brief summary of the main studies on anti-C5 therapy for AKI, including doses, administration times, and effects on mitochondrial parameters (if measured). Currently, Section 5 provides a list of available drugs rather than a comparative assessment of their effectiveness.

Author Response

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