Mitochondrial Control of Cellular Life, Stress, and Death

Abstract

Since the discovery that mitochondrial membrane permeabilization represents a critical step in the regulation of intrinsic apoptosis, mitochondria have been viewed as pluripotent organelles, controlling cell death as well as several aspects of cell survival. Mitochondria constitute the most prominent source of ATP and are implicated in multiple anabolic and catabolic circuitries. In addition, mitochondria coordinate cell-wide stress responses, such as autophagy, and control nonapoptotic cell death routines, such as regulated necrosis. Thus, mitochondria seem to regulate a continuum of cellular functions, spanning from physiological metabolism to stress responses and death. The involvement of mitochondria in both vital and lethal processes is crucial for both embryonic and postembryonic development, as well as for the maintenance of adult tissue homeostasis. In line with this notion, primary mitochondrial defects or alterations in the signaling pathways that converge on or emanate from mitochondria underpin a large number of human diseases, including premature aging, neurodegenerative disorders, cardiovascular disorders, and cancer. Here, we provide an overview of the molecular mechanisms that enable mitochondria to sustain cell survival, coordinate stress responses, and mediate cell death, linking these pathways—whenever relevant—to cardiovascular health and disease.

Platelets induce apoptosis via membrane-bound FasL

“…7,61 In contrast to uncontrolled tissue damage, programmed cell death is an important mechanism to maintain tissue homeostasis. 15,17,18,62,63 In the context of sepsis, Clark et al 64 found that PLT interaction with neutrophils can mediate endothelial damage in the presence of lipopolysaccharide. Although cell damage was measured by PI uptake, endothelial apoptosis was not assessed.…”

Essential role for autophagy in life span extension

“…This mechanism might ensure that cellular damage can be cleared by autophagy before it induces unwarranted cell death, especially in post-mitotic cells like neurons (93). As described above, the autophagic machinery can also detect and dispose damaged mitochondria that otherwise release pro-apoptotic factors and harmful reactive oxygen species, thereby offering cellular self-rescue (94). This mechanism might contribute to the commonly observed increase of autophagy in skeletal muscle myopathies.…”

Consensus guidelines for the detection of immunogenic cell death

“…[239][240][241] The externalization of phosphatidylserine (a phospholipid normally restricted to the inner leaflet of the plasma membrane) indeed accompanies multiple (though not all) instances of apoptotic cell death, 16,[242][243][244][245] while the permanent dissipation of the Dc m as a result of mitochondrial outer membrane permeabilization (MOMP) constitutes one of the major hallmarks of mitochondrial apoptosis. 17,18,246,247 Of note, DiOC 6 (3) is not compatible with fixation, but other Dc m -sensitive probes are, including chloromethyltetramethylrosamine (absorption/emission peaks: 554/576 nm). 248 MOMP is accompanied by the massive activation of caspase-9 and -3, while caspase-8 is required for ICD upstream of MOMP.…”