The mitochondrial permeability transition initiates autophagy in rat hepatocytes

  title={The mitochondrial permeability transition initiates autophagy in rat hepatocytes},
  author={Steven P. Elmore and Ting Qian and Sherry F. Grissom and John J. Lemasters},
  journal={The FASEB Journal},
Cells degrade excess and effete organelles by the process of autophagy. Autophagic stimulation of rat hepatocytes by serum deprivation and glucagon (1 µM) caused a fivefold increase of spontaneously depolarizing mitochondria to about 1.5% of total mitochondria after 90 min. Cyclosporin A (CsA, 5 µM), an immunosuppressant that blocks the mitochondrial permeability transition (MPT), prevented this depolarization. Depolarized mitochondria moved into acidic vacuoles labeled by LysoTracker Red… 

Impaired autophagy: A mechanism of mitochondrial dysfunction in anoxic rat hepatocytes

Calpain 2–mediated degradation of Atg7 and Beclin‐1 impairs mitochondrial autophagy, and this subsequently leads to MPT‐dependent hepatocyte death after A/R, which was reversed by nutrient depletion and adenoviral overexpression.

Cyclophilin D is required for mitochondrial removal by autophagy in cardiac cells

A physiologic function for CypD and the MPT in the regulation of starvation-induced autophagy is suggested and may represent a homeostatic mechanism for cellular and mitochondrial quality control.

Roles of mitophagy and the mitochondrial permeability transition in remodeling of cultured rat hepatocytes

Findings indicate that mitochondrial autophagy (mitophagy) and the MPT underlie mitochondrial remodeling in cultured hepatocytes.

Role of mitochondrial inner membrane permeabilization in necrotic cell death, apoptosis, and autophagy.

A new term, necrapoptosis, describes such death processes that begin with a common stress or death signal, progress by shared pathways, but culminate in either cell lysis (necrosis) or programmed cellular resorption (apoptosis), depending on modifying factors such as ATP.

Selective mitochondrial autophagy, or mitophagy, as a targeted defense against oxidative stress, mitochondrial dysfunction, and aging.

The term "mitophagy" is proposed to emphasize the non-random nature of the selective autophagy of mitochondria and may play a key role in retarding accumulation of somatic mutations of mtDNA with aging.

Bnip3-mediated mitochondrial autophagy is independent of the mitochondrial permeability transition pore

The results support a model where Bnip3 induces selective removal of the mitochondria in cardiac myocytes, and that BnIP3 triggers induction of autophagy independent of Ca2+, ROS generation, and mPTP opening.

Tubular network formation protects mitochondria from autophagosomal degradation during nutrient starvation

It is demonstrated that mitochondrial elements become significantly elongated and interconnected shortly after nutrient depletion, and it is established that mitochondrial tubulation upon nutrient deprivation protects mitochondria from autophagosomal degradation, which could permit mitochondria to maximize energy production and supply autophagic membranes during starvation.

Tracker Dyes to Probe Mitochondrial Autophagy (Mitophagy) in Rat Hepatocytes

The results show that mitochondria once selected for mitophagy are rapidly digested and support the concept that mitochondrial autophagy involves the MPT and signaling through PI3 kinase and possibly JNK.



Response of autophagic protein degradation to physiologic and pathologic stimuli in rat hepatocyte monolayer cultures.

  • Q. YuL. Marzella
  • Biology, Medicine
    Laboratory investigation; a journal of technical methods and pathology
  • 1988
The data indicate that in physiologic conditions, increases in numbers of hepatocyte lysosomes reflect increased sequestration and degradation of cytoplasmic proteins in response to changes in the levels of hormones, serum factors and nutrients.

The Mitochondrial Permeability Transition Is Required for Tumor Necrosis Factor Alpha-Mediated Apoptosis and Cytochrome c Release

The MPT is an essential component in the signaling pathway for TNFα-induced apoptosis in hepatocytes which is required for both cytochrome c release and cell death and functions downstream of FADD and crmA but upstream of caspase 3.

Contribution of the mitochondrial permeability transition to lethal injury after exposure of hepatocytes to t-butylhydroperoxide.

The permeability transition pore does not 'flicker' open during normal incubation of hepatocytes but remains continuously closed, and mitochondrial depolarization per se does not cause the permeability Transition in intact cells.

Autophagy Is Activated by Apoptotic Signalling in Sympathetic Neurons: An Alternative Mechanism of Death Execution

It is proposed that the same apoptotic signals that cause mitochondrial dysfunction also activate autophagy, a mechanism whereby cells digest themselves from within and so may be used in lieu of apoptosis to execute cell death.

V. Necrapoptosis and the mitochondrial permeability transition: shared pathways to necrosis and apoptosis.

  • J. Lemasters
  • Biology
    American journal of physiology. Gastrointestinal and liver physiology
  • 1999
The term "necrapoptosis" is introduced to emphasize the shared pathways leading to both forms of cell death in apoptotic and necrotic cell death after death signals and toxic stresses.

Nonselective autophagy of cytosolic enzymes by isolated rat hepatocytes

The experiments suggest that sequestration and degradation of normal cytosolic proteins by the autophagic-lysosomal pathway is a nonselective bulk process, and that nonautophagic mechanisms must be invoked to account for differential enzyme turnover.

ATP depletion rather than mitochondrial depolarization mediates hepatocyte killing after metabolic inhibition.

Protection by fructose against toxicity of cyanide, oligomycin, and CCCP was mediated by glycolytic ATP formation rather than by preservation of the mitochondrial membrane potential, supporting the hypothesis that inhibition of cellular ATP formation is a crucial event in the progression of irreversible cell injury.

Inhibition by insulin of the formation of autophagic vacuoles in rat liver. A morphometric approach to the kinetics of intracellular degradation by autophagy

The results indicate that autophagy, to some extent, is selective and plays an important, but not an exclusive, role in intracellular turnover.

Studies on cellular autophagocytosis. Cyclic AMP- and dibutyryl cyclic AMP-stimulated autophagy in rat liver.

Findings constitute preliminary evidence that glucagon-stimulated autophagy is mediated at least in part by cyclic AMP.

Action of cyclosporine on mitochondrial calcium fluxes

It is shown that cyclosporine exhibits an inhibitory effect upon mitochondrial respiration, in good agreement with previous works and may be correlated with Cys A toxicity.