Mitochondrial Extrusion through the Cytoplasmic Vacuoles during Cell Death

Abstract

Under various conditions, noxious stimuli damage mitochondria, resulting in mitochondrial fragmentation; however, the mechanisms by which fragmented mitochondria are eliminated from the cells remain largely unknown. Here we show that cytoplasmic vacuoles originating from the plasma membrane engulfed fragmented mitochondria and subsequently extruded them into the extracellular spaces in undergoing acute tumor necrosis factor ␣-induced cell death in a caspase-dependent fashion. Notably, upon fusion of the membrane encapsulating mitochondria to the plasma membrane, naked mitochondria were released into the extracellular spaces in an exocytotic manner. Mitochondrial extrusion was specific to tumor necrosis factor ␣-induced cell death, because a genotoxic stress-inducing agent such as cisplatin did not elicit mitochondrial extrusion. Moreover, intact actin and tubulin cytoskeletons were required for mitochondrial extrusion as well as membrane blebbing. Furthermore, fragmented mitochondria were engulfed by cytoplasmic vacuoles and extruded from hepatocytes of mice injected with anti-Fas antibody, suggesting that mitochondrial extrusion can be observed in vivo under pathological conditions. Mitochondria are eliminated during erythrocyte maturation under physiological conditions, and anti-mitochondrial antibody is detected in some autoimmune diseases. Thus, elucidating the mechanism underlying mitochondrial extrusion will open a novel avenue leading to better understanding of various diseases caused by mitochondrial malfunction as well as mitochondrial biology.

Extrusion of mitochondrial contents from lipopolysaccharide-stimulated cells: Involvement of autophagy

“…Nakajima et al have reported that fragmented mitochondria in MEFs deficient in CFLAR/c-flip (cflar ¡/¡ MEFs) are released through a mechanism mediated by an endocytosis-exocytosis pathway during the course of apoptosis elicited by TNF. 46 However, the autophagy machinery has proved not to be involved in this case, as 3MA has no effect. 46 To the best of our knowledge, our report is the first to demonstrate mitochondrial extrusion from LPS-stimulated cells through the autophagy machinery.…”

“…46 However, the autophagy machinery has proved not to be involved in this case, as 3MA has no effect. 46 To the best of our knowledge, our report is the first to demonstrate mitochondrial extrusion from LPS-stimulated cells through the autophagy machinery. Recent research has indicated that the final point of autophagy is not always lysosomal degradation.…”

Induction of Type I IFN Is a Physiological Immune Reaction to Apoptotic Cell-Derived Membrane Microparticles

“…4A). Considering recent reports that mitochondria are expulsed in early apoptosis (53) and that mtDNA stimulates either TLR9 in inflammation and transplant rejection (49,50) or, alternatively, the AIM2 inflammasome and/ or caspase-1 in sepsis (51), we initially argued that the pronounced immunostimulatory activity of MMP DNA could be attributed to selective accumulation of mtDNA in MMP derived from apoptotic cells (Fig. 5A).…”

Mitochondrial quality control in the myocardium: Cooperation between protein degradation and mitophagy

“…In addition, Nakajime et al found that fragmented mitochondria were sequestered in vacuoles that originated from the plasma membrane in cultured c-flip−/− mouse embryonic fibroblasts undergoing apoptosis [78]. These vesicles fused with the plasma membrane, resulting in the release of naked mitochondria into the extracellular space.…”