Mitoxyperilysis: A Milestone Discovery in the Field of Cell Death

Abstract

In a recent study published in Cell, Wang and colleagues unveiled a previously unrecognized form of lytic cell death, termed “mitoxyperilysis,” triggered by mitochondria-induced oxidative damage (Figure 1a) [1]. This work not only provides critical insights into how mitochondrial dysfunction and oxidative stress drive pathogenesis but also presents a potential strategy for treating oxidative stress-associated diseases.

Metabolic homeostasis is crucial for both cells and organisms, and metabolic dysregulation contributes to diverse pathologies, including cancer, non-alcoholic fatty liver disease, and diabetes [2]. Innate immune activation and metabolic disruption (IIAMD) often occur simultaneously and jointly drive disease progression. For example, malignant cells undergo metabolic reprogramming characterized by lactate accumulation and hypoxia [3]. The metabolic alterations promote the release of damage-associated molecular patterns (DAMPs), initiate innate immune pathways (e.g., TLR and NLRP3), and finally lead to various forms of cell death (Figure 1b,c) [2]. Cell death accompanied by impaired membrane integrity and the release of cellular contents further amplifies inflammatory cascades, establishing a feed-forward loop of DAMP release—inflammation—cell death, ultimately resulting in a pathological state [2]. Although mitochondrial oxidative stress is implicated in various cell death pathways, the mechanisms by which it drives membrane lysis, particularly under IIAMD, remain poorly understood. This necessitates a deeper investigation into how mitochondrial state dictates cell fate and fuels disease progression.

To mimic IIAMD, Wang Y and colleagues treated bone-marrow-derived macrophages (BMDMs) with innate immune stimulants, including PAM3, LPS, R848, and Poly[I:C] under carbon starvation (CS) [1]. Interestingly, neither innate immune activation nor CS-induced metabolic stress alone induced cell death. However, in the presence of CS, all stimulants except Poly[I:C] triggered robust lytic cell death, characterized by the release of plasma membrane rupture markers LDH and HMGB1, with LPS exhibiting the strongest effect. Consistently, the supplementation of glucose, glutamine, or pyruvate alone suppressed cell death induced by IIAMD. These findings suggest that innate immune triggering and metabolic stress are necessary and sufficient to induce cell death.

The most disruptive aspect of this work is the unveiling of mitoxyperilysis. To investigate whether cell death under IIAMD is induced by canonical pathways, the genetic ablation of key executioners of apoptosis (e.g., Caspase-9), pyroptosis (e.g., NLRP3 and Gasdermin family members such as GSDMD, GSDME, and GSDMC4), and necroptosis (e.g., MLKL) was performed [1]. However, the genetic ablation did not markedly attenuate IIAMD-induced membrane rupture. Beyond canonical pathways, NINJ1, a molecule recently reported to mediate plasma membrane rupture and DAMP release [4], did not appear to contribute under these conditions as its knockdown failed to alleviate cell death. Furthermore, the individual or combined use of serial cell death inhibitors, such as the pan-caspase inhibitor z-VAD, the necroptosis inhibitor Nec-1s, and the ferroptosis inhibitor Fer-1, did not decrease LPS + CS-induced cell death. These findings strongly indicate that IIAMD-induced cell death is distinct from previously known pathways.

This new cell death pathway was termed mitoxyperilysis due to the critical role of mitochondrial oxidative stress in driving membrane lysis [1]. Specifically, under IIAMD, an aberrant retention of mitochondria at the plasma membrane was observed (Figure 1a). Meanwhile, sustained local oxidative events at sites of mitochondria-membrane contact were also observed through live-cell imaging, followed by subsequent membrane rupture, as evidenced by Sytox Green uptake kinetics. The above process is defined as “mitoxyperiosis.” These observations indicate that mitochondrial arrest and local oxidative attack ultimately compromise membrane integrity.

A subsequent drug screening confirmed a critical role of the mTOR pathway in mitoxyperilysis, as the inhibitor used to block mTORC2 function in this context, Torin‑1, markedly reduced IIAMD-induced cell death [1]. Mechanistically, under IIAMD, mTORC2 signaling aberrantly suppresses actin polymerization, thereby inhibiting cytoskeletal dynamics and trapping mitochondria at the plasma membrane (Figure 1a). Notably, in most physiological contexts (e.g., dendritic neuronal spines, migrating fibroblasts), mTORC2 is viewed as a promoter of F-actin stability and polymerization. For instance, mTORC2 deficiency has been shown to hinder actin polymerization in the hippocampus, thereby impairing long-term memory and causing cognitive dysfunction in mice [5]. These findings indicate an abnormal state of mTORC2 under IIAMD, distinct from its basal role as a promoter of actin polymerization.

Furthermore, inhibiting mTORC2 restored actin dynamics to release trapped mitochondria and prevent localized membrane rupture, without reducing overall oxidative stress, strongly suggesting that localized oxidative stress is necessary to trigger mitoxyperilysis.

Consequently, mitoxyperilysis is defined by three characteristics: a dual trigger of immune and metabolic stress, pathological mitochondrial retention at the plasma membrane, and localized oxidative damage preceding rupture.

Beyond mechanism, the study offers an application potential of mitoxyperilysis in cancer treatment. In a syngeneic B16 melanoma model, intratumoral injection of low-dose LPS in conjunction with fasting markedly reduced tumor size in C57BL/6 mice, while LPS administration or fasting alone failed to achieve a similar effect. These findings suggest that the utilization of IIAMD-induced mitoxyperilysis may improve the therapeutic effect of anti-tumor treatment.

Together, Wang Y et al. unveiled a previously unknown cell death—mitoxyperilysis, elucidating the molecular mechanism induced by mTORC2 and providing a potential application of mitoxyperilysis in disease treatment.

In addition, this study leaves several intriguing questions for future investigation. First, although this study compared mitochondrial membrane potential across different cell death pathways (Figure 1a–c), the exact molecular mechanisms underlying these distinct potentials remain unclear. Second, apart from cancer, other diseases such as diabetes and non-alcoholic fatty liver disease also involve IIAMD, and whether mitoxyperilysis is involved in the pathogenesis requires further research.

Cell death is involved in the pathogenesis of multiple diseases (Figure 1d), and the discovery of mitoxyperilysis represents a major conceptual advance in the field of cell death. Further delineation of the links between cell death pathways and disease will deepen our understanding of the molecular mechanisms underlying pathogenesis and facilitate the development of more effective therapeutics.

P.J. designed the project (conceptualization). Y.N. and P.J. read the papers and analyzed the data (formal analysis). M.L. and P.J. wrote and revised the manuscript (Writing – original draft and review and editing). M.L. drew the figure (visualization). All authors have read and approved the final manuscript.

The authors declare no conflicts of interest.

The authors have nothing to report.

The authors have nothing to report. No copyrighted software or websites were used in the visualization process, and all elements and images were created by M.L. using Procreate and Adobe Illustrator.