Deciphering the Molecular Nexus: An In-Depth Review of Mitochondrial Pathways and Their Role in Cell Death Crosstalk

Abstract

Cellular demise is a pivotal event in both developmental processes and disease states, with mitochondrial regulation playing an essential role. Traditionally, cell death was categorized into distinct types, considered to be linear and mutually exclusive pathways. However, the current understanding has evolved to recognize the complex and interconnected mechanisms of cell death, especially within apoptosis, pyroptosis, and necroptosis. Apoptosis, pyroptosis, and necroptosis are governed by intricate molecular pathways, with mitochondria acting as central decision-makers in steering cells towards either apoptosis or pyroptosis through various mediators. The choice between apoptosis and necroptosis is often determined by mitochondrial signaling and is orchestrated by specific proteins. The molecular dialogue and the regulatory influence of mitochondria within these cell death pathways are critical research areas. Comprehending the shared elements and the interplay between these death modalities is crucial for unraveling the complexities of cellular demise.

Keywords: apoptosis; mitochondria; necroptosis; pyroptosis.

Figure 1

Components within each PCD pathway that are regulated by mitochondria. (The figure illustrates the key proteins and pathways regulated by mitochondria within the respective routes of apoptosis, pyroptosis, and necroptosis. In the apoptotic pathway, mitochondria mainly promote the formation of apoptotic bodies and the cascade amplification reaction of the caspase family by releasing cytochrome C, which eventually leads to apoptosis. In the pyroptosis pathway, mitochondria influence cell death by regulating ATP synthesis, which activates NLRP3 and caspase-3, ultimately leading to the cleavage of GSDME. In the necroptosis pathway, damaged mitochondria release ROS, which further promotes the binding and phosphorylation of RIPK1 and RIPK3, followed by the aggregation and phosphorylation of MLKL, resulting in necroptotic cell death).

Figure 2

The intersection of apoptosis and pyroptosis is regulated by mitochondria. a. Exogenous apoptosis pathway: ligand/Death receptor/FADD/Pro-caspase-8 binds at the plasma membrane and mediates apoptosis through the downstream Caspase 8/CASP3/PARP pathway; b. Endogenous apoptosis pathway: under the stimulation of endogenous factors such as DNA damage/ER stress/metabolic stress, mitochondria undergo MOMP through the mitochondrial pro-apoptotic proteins BAX/BAK/BAD, and then apoptosis is mediated through the downstream cytochrome C/apaf-1/Caspase 9/Caspase 3/PARP pathway; c. Classical pyroptosis pathway: upon PAMP/DAMP stimulation, NLRP3/ASC/Pro-caspase-1 forms pyroptosis vesicles, which mediate pyroptosis via active Caspase 1 to activate Pro-IL-1/Pro-IL-18 and cleave GSDMD; d. Non-classical pyroptosis pathway: the presence of intracellular LPS contributes to the occurrence of Caspase 4/11/GSDMD-associated pyroptosis; e. Intersecting pathways of apoptosis/pyroptosis regulated by mitochondria: elevated intracellular Iron causes mitochondria to mediate the onset of pyroptosis via the elevated ROS/Tom20 oligomerization/BAX/MOMP/cytochrome C release/apaf-1/Caspase 9/Caspase 3/GSDME pathways. Caspase 1 in pyroptosis vesicles can mediate pyroptosis via the mitochondrial pro-apoptotic protein t BID/apaf-1/Caspase 9/Caspase 3/GSDME pathway. High expression of HK-II inhibits both the pathway of cells toward cytochrome C/apaf-1/Caspase 9/Caspase 3/PARP-associated pyroptosis and the pathway of cells toward the cytochrome C/apaf-1/Caspase 9/Caspase 3/GSDME-associated pyroptosis pathway, and Triptolide inhibits the expression of HK-II. Inactivation of mitochondrial anti-apoptotic proteins such as Mcl-1 and Bcl-xL instead led to mitochondrial-mediated pyroptosis via the MOMP/cytochrome C release/apaf-1/Caspase 9/Caspase 3/GSDME pathway. Bcl-2 can inhibit pyroptosis by interacting with Caspase 1, which enhances GSDMD cleavage at the D87 site. In the presence of high bile acid levels, LND, and ANT1, mitochondria mediate pyroptosis via MPT/cytochrome C/Apaf-1/Caspase 4/Caspase 3/GSMDE.

Figure 3

Intersection of apoptosis and necroptosis regulated by mitochondria. a. Endogenous apoptosis pathway: When cells are stimulated by endogenous factors such as DNA damage/ER stress/metabolic stress, the mitochondrial pro-apoptotic proteins BAX/BAK/BAD lead to the occurrence of MOMP, and then apoptosis is mediated by downstream cytochrome C/apaf-1/Caspase 9/Caspase 3/PARP. During the process of apoptosis, mitochondria release proteases or pro-apoptotic factors such as AIF, Endo G, HtrA2 to enhance apoptosis. b. Exogenous apoptotic pathway: ligand/Death receptor/FADD/Pro-caspase-8 binds at the plasma membrane and mediates apoptosis through the downstream CASP8/CASP3/PARP pathway. c. Necroptosis pathway: TNF-a binds to TNFR1/RIPK1/TRADD/TRAF2/CIAP1/2 at the plasma membrane, which activates the formation of necrosomes (RIPK1/FADD/Pro-Caspase-8/FILP) and further promotes downstream aggregation and phosphorylation of RIPK1/RIPK3 and MLKL. This ultimately contributes to necroptosis. d. Intersecting pathways of apoptosis/necroptosis regulated by mitochondria: stimulated by TNF-a, the pro-apoptotic protein PUMA on the mitochondrial membrane can also cause the mitochondria to release mtDNA, leading to necroptosis via the DAI/Zbp1/STING/P-RIPK3/P-MLKL pathway. P-RIPK3/P-MLKL can, in turn, further enhance PUMA expression. Elevated expression of Zbp1 can also trigger necroptosis via the NOXA/MLKL pathway. HtrA2 can inhibit apoptosis via Bcl-2. On the other hand, in DSS-induced colitis, HtrA2 can also lead to necroptosis via RIPK1. Under conditions of vitamin K3 exposure, mitochondria-released AIF and Endo G translocated to the nucleus, and the cells exhibited a necroptosis morphology. Under stress conditions such as Pristimerin, cells can upregulate the BAX/Bcl-2 ratio, produce excess ROS, and translocate AIF to the nucleus, culminating in chromatin cleavage. Cells undergo necroptosis. Knockdown of the pro-apoptotic proteins BAX/BAK/BID can lead to necroptosis by increasing the expression of RIPK1.

Figure 4

Intersection molecules of the mitochondrially regulated PCD pathway.