Blocking reverse electron transfer-mediated mitochondrial DNA oxidation rescues cells from PANoptosis

Shi, Fu-li; Li, Qing; Xu, Rong; Yuan, Li-sha; Chen, Ying; Shi, Zi-jian; Li, Ya-ping; Zhou, Zhi-ya; Xu, Li-hui; Zha, Qing-bing; Hu, Bo; He, Xian-hui; Ou-yang, Dong-yun

doi:10.1038/s41401-023-01182-8

Cited by 8 publications

(4 citation statements)

References 65 publications

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“…Future work should determine whether PP6 and its subunits cooperate with PP1γ to regulate TAK1i-induced PANoptosis and whether the effect of PP6 on RIPK1 phosphorylation is direct or indirect. Additionally, a recent study has reported that the excessive production of mitochondrial ROS (mtROS) through reverse electron transport (RET) drives PANoptosis [ 45 ]. Pre-treatment with anti-RET reagents such as 1-methoxy PMS or dimethyl fumarate blocks RET-mediated mitochondrial ROS production and subsequent induction of PANoptotic cell death in BMDMs [ 45 ].…”

Section: Discussionmentioning

confidence: 99%

“…Additionally, a recent study has reported that the excessive production of mitochondrial ROS (mtROS) through reverse electron transport (RET) drives PANoptosis [ 45 ]. Pre-treatment with anti-RET reagents such as 1-methoxy PMS or dimethyl fumarate blocks RET-mediated mitochondrial ROS production and subsequent induction of PANoptotic cell death in BMDMs [ 45 ]. Further studies will be needed to determine the role of mtROS in TAK1i-induced cell death.…”

Section: Discussionmentioning

confidence: 99%

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The protein phosphatase PP6 promotes RIPK1-dependent PANoptosis

Bynigeri,

Malireddi,

Mall

et al. 2024

BMC Biol

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Background The innate immune system serves as the first line of host defense. Transforming growth factor-β–activated kinase 1 (TAK1) is a key regulator of innate immunity, cell survival, and cellular homeostasis. Because of its importance in immunity, several pathogens have evolved to carry TAK1 inhibitors. In response, hosts have evolved to sense TAK1 inhibition and induce robust lytic cell death, PANoptosis, mediated by the RIPK1-PANoptosome. PANoptosis is a unique innate immune inflammatory lytic cell death pathway initiated by an innate immune sensor and driven by caspases and RIPKs. While PANoptosis can be beneficial to clear pathogens, excess activation is linked to pathology. Therefore, understanding the molecular mechanisms regulating TAK1 inhibitor (TAK1i)-induced PANoptosis is central to our understanding of RIPK1 in health and disease. Results In this study, by analyzing results from a cell death-based CRISPR screen, we identified protein phosphatase 6 (PP6) holoenzyme components as regulators of TAK1i-induced PANoptosis. Loss of the PP6 enzymatic component, PPP6C, significantly reduced TAK1i-induced PANoptosis. Additionally, the PP6 regulatory subunits PPP6R1, PPP6R2, and PPP6R3 had redundant roles in regulating TAK1i-induced PANoptosis, and their combined depletion was required to block TAK1i-induced cell death. Mechanistically, PPP6C and its regulatory subunits promoted the pro-death S166 auto-phosphorylation of RIPK1 and led to a reduction in the pro-survival S321 phosphorylation. Conclusions Overall, our findings demonstrate a key requirement for the phosphatase PP6 complex in the activation of TAK1i-induced, RIPK1-dependent PANoptosis, suggesting this complex could be therapeutically targeted in inflammatory conditions.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The protein phosphatase PP6 promotes RIPK1-dependent PANoptosis

Bynigeri,

Malireddi,

Mall

et al. 2024

BMC Biol

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“…SDH is linked to two important physiological metabolic processes: the TCA cycle and OXPHOS (Du et al, 2023 ). Decreased activity of SDH leads to the accumulation of succinate, which is rapidly oxidized, driving ROS generation through reverse electron transfer to complex I, resulting in PANoptosis in cells (Chouchani et al, 2014 ; Shi et al, 2023b ). This phenomenon is reversed by reverse electron transfer inhibitors (Shi et al, 2023b ).…”

Section: Mitochondria Play a Crucial Role In Initiating Panoptosismentioning

confidence: 99%

Neurotoxic β-amyloid oligomers cause mitochondrial dysfunction—the trigger for PANoptosis in neurons

Meng,

Song,

Liu

et al. 2024

Front. Aging Neurosci.

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As the global population ages, the incidence of elderly patients with dementia, represented by Alzheimer's disease (AD), will continue to increase. Previous studies have suggested that β-amyloid protein (Aβ) deposition is a key factor leading to AD. However, the clinical efficacy of treating AD with anti-Aβ protein antibodies is not satisfactory, suggesting that Aβ amyloidosis may be a pathological change rather than a key factor leading to AD. Identification of the causes of AD and development of corresponding prevention and treatment strategies is an important goal of current research. Following the discovery of soluble oligomeric forms of Aβ (AβO) in 1998, scientists began to focus on the neurotoxicity of AβOs. As an endogenous neurotoxin, the active growth of AβOs can lead to neuronal death, which is believed to occur before plaque formation, suggesting that AβOs are the key factors leading to AD. PANoptosis, a newly proposed concept of cell death that includes known modes of pyroptosis, apoptosis, and necroptosis, is a form of cell death regulated by the PANoptosome complex. Neuronal survival depends on proper mitochondrial function. Under conditions of AβO interference, mitochondrial dysfunction occurs, releasing lethal contents as potential upstream effectors of the PANoptosome. Considering the critical role of neurons in cognitive function and the development of AD as well as the regulatory role of mitochondrial function in neuronal survival, investigation of the potential mechanisms leading to neuronal PANoptosis is crucial. This review describes the disruption of neuronal mitochondrial function by AβOs and elucidates how AβOs may activate neuronal PANoptosis by causing mitochondrial dysfunction during the development of AD, providing guidance for the development of targeted neuronal treatment strategies.

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“…Shi et al ( 124 ) explored the roles of mitochondrial ROS (mtROS) and reverse electron transport (RET) in the induction of PANoptosis and showed that anti-RET reagents such as 1-methoxy PMS (a stable electron transfer mediator in CCK-8 kits) and dimethyl fumarate can effectively inhibit PANoptosis by blocking mtROS production. In a related context, Yuan et al ( 125 ) used a multi specific platinum complex SEP, which was constructed by conjugating a quinone derivative seratrodast to a prodrug of cisplatin, as the first metal complex capable of inducing PANoptosis in KRAS-mutant pancreatic ductal adenocarcinoma cells, offering a novel strategy to overcome apoptotic resistance.…”

Section: Panoptosismentioning

confidence: 99%

PANoptosis: Novel insight into regulated cell death and its potential role in cardiovascular diseases (Review)

Gao,

Ma,

Liang

et al. 2024

Int J Mol Med

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PANoptosis, a complex form of proinflammatory programmed cell death, including apoptosis, pyroptosis and necroptosis, has been an emerging concept in recent years that has been widely reported in cancer, infectious diseases and neurological disorders. Cardiovascular diseases (CVDs) are an important global health problem, posing a serious threat to individuals' lives. An increasing body of research shows that inflammation has a pivotal role in CVDs, which provides an important theoretical basis for PANoptosis to promote the progression of CVDs. To date, only sporadic studies on PANoptosis in CVDs have been reported and its role in the field of CVDs has not been fully explored. Elucidating the various modes of cardiomyocyte death, the specific molecular mechanisms and the links among the various modes of death under various stressful stimuli is of notable clinical significance for a deeper understanding of the pathophysiology of CVDs. The present review summarizes the molecular mechanisms of apoptosis, pyroptosis, necroptosis and PANoptosis and their prospects in the field of CVDs.

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Blocking reverse electron transfer-mediated mitochondrial DNA oxidation rescues cells from PANoptosis

Cited by 8 publications

References 65 publications

The protein phosphatase PP6 promotes RIPK1-dependent PANoptosis

The protein phosphatase PP6 promotes RIPK1-dependent PANoptosis

Neurotoxic β-amyloid oligomers cause mitochondrial dysfunction—the trigger for PANoptosis in neurons

PANoptosis: Novel insight into regulated cell death and its potential role in cardiovascular diseases (Review)

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