Novel mechanism of elimination of malfunctioning mitochondria (mitoptosis): Formation of mitoptotic bodies and extrusion of mitochondrial material from the cell

Abstract

Energy catastrophe, when mitochondria hydrolyze glycolytic ATP instead of producing respiratory ATP, has been modeled. In highly glycolyzing HeLa cells, 30-50% of the population survived after inhibition of respiration and uncoupling of oxidative phosphorylation for 2-4 days. The survival was accompanied by selective elimination of mitochondria. This type of mitoptosis includes (i) fission of mitochondrial filaments, (ii) clustering of the resulting roundish mitochondria in the perinuclear area, (iii) occlusion of mitochondrial clusters by a membrane (formation of a "mitoptotic body"), (iv) decomposition of mitochondria inside this body to small membrane vesicles, (v) protrusion of the body from the cell, and (vi) disruption of the body boundary membrane. Autophagy was not involved in this mitoptotic program. Increased production of reactive oxygen species (ROS) was necessary for execution of the program, since antioxidants prevent mitoptosis and kill the cells treated with the mitochondrial poisons as if a ROS-linked mitoptosis serves for protection of the cells under conditions of severe mitochondrial stress. It is suggested that exocytosis of mitoptotic bodies may be involved in maturation of reticulocytes and lens fiber cells.

Mitochondrial Extrusion through the Cytoplasmic Vacuoles during Cell Death

“…A very recent study has shown that ROS might be involved in mitochondrial extrusion (21). As we previously reported (13), TNF␣ induced robust ROS accumulation in c-Flip Ϫ/Ϫ MEFs (Fig.…”

Mitoptosis, a Novel Mitochondrial Death Mechanism Leading Predominantly to Activation of Autophagy

“…Such observations are further supported by studies using mitochondrial respiratory chain uncouplers and mitochondrial poisons in which overproduction of ROS could be observed without reductions in cellular ATP levels leading to mitoptosis (20). The specific removal of dysfunctional or ROS-overproducing mitochondria during apoptosis or mitoptosis is believed to be achieved by autophagy either by autophagosome formation (mitophagy) or by the formation of mitoptot- ic bodies that are subsequently released into the extracellular environment (19). The elimination of dysfunctional mitochondria is further supported by studies of cells treated with staurosporin, a common drug used to induce apoptosis, and by the use of pan-caspase inhibitors in which cells survive but lose their mitochondria (21).…”

Autophagy, Apoptosis, Mitoptosis and Necrosis: Interdependence Between Those Pathways and Effects on Cancer

“…Induction of mitoptosis and concomitant disruption of ATP supply by mitochondria are often followed by activation of autophagy to assure maintenance of energy supply (Fig. 3, left panels) (Jangamreddy and Los 2012;Mijaljica et al 2010 2012)], or the mitoptotic bodies may be extruded from the cell (Lyamzaev et al 2008). During the ''outer mitochondrial membrane mitoptosis'', the mitochondria undergo condensation, followed by swelling and fragmenting of cristae, and finally the outer mitochondrial membrane bursts with vesicular remnants of cristae floating in the cytoplasm.…”