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Review
, 333 (6046), 1109-12

Mitochondria and the Autophagy-Inflammation-Cell Death Axis in Organismal Aging

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Review

Mitochondria and the Autophagy-Inflammation-Cell Death Axis in Organismal Aging

Douglas R Green et al. Science.

Abstract

Alterations of mitochondrial functions are linked to multiple degenerative or acute diseases. As mitochondria age in our cells, they become progressively inefficient and potentially toxic, and acute damage can trigger the permeabilization of mitochondrial membranes to initiate apoptosis or necrosis. Moreover, mitochondria have an important role in pro-inflammatory signaling. Autophagic turnover of cellular constituents, be it general or specific for mitochondria (mitophagy), eliminates dysfunctional or damaged mitochondria, thus counteracting degeneration, dampening inflammation, and preventing unwarranted cell loss. Decreased expression of genes that regulate autophagy or mitophagy can cause degenerative diseases in which deficient quality control results in inflammation and the death of cell populations. Thus, a combination of mitochondrial dysfunction and insufficient autophagy may contribute to multiple aging-associated pathologies.

Figures

Figure 1
Figure 1. Interactions between mitochondria, cell death, autophagy, and inflammation in young individuals (a) and during aging (b)
In this scenario, loss of autophagy with age leads to accumulation of damaged mitochondria, which promote cell death and inflammation, both of which are otherwise limited by autophagy.
Figure 2
Figure 2. Mechanisms of mitophagy
In healthy mitochondria (a), PINK1 is actively imported by a mitochondrial transmembrane potential (Δψm)-dependent mechanism and degraded by the inner mitochondrial membrane protease PARL. BCL-2 and BCL-XL bind to and inhibit Beclin 1. Different triggers can stimulate distinct pathways to mitophagy (b). The BH3-only proteins NIX and BNIP3 are activated during erythroblast differentiation and under hypoxia, respectively, and may cause mitophagy by displacing Beclin 1 from inhibitory interactions with BCL-2 and BCL-XL. In response to uncoupling, mitochondrial damage or the mitochondrial permeability transition (MPT), the Δψm is dissipated and full length PINK1 accumulates at the outer mitochondrial membrane (OM). This allows for the recruitment of the AAA ATPase p97 and of Parkin, which together render mitochondria a palatable substrate for the autophagic machinery. Mitochondrial turnover can also be mediated by accumulation of AMP, leading to the phosphorylation of ULK1 by AMPK and possibly involving a ATG12-ATG3 conjugate that functions specifically in mitophagy.
Figure 3
Figure 3. Mitophagy exerts cytoprotective effects by intercepting lethal signals before or at the level of mitochondria
In response to lethal stimuli, mitochondria can undergo BAX- or BAK-mediated mitochondrial outer membrane permeabilization (MOMP), or activate the permeability transition pore complex (PTPC), driving the mitochondrial permeability transition (MPT). In both instances, intermembrane space proteins (IMS) are released into the cytosol where they activate caspase-dependent and -independent mechanisms that mediate cell death. One MPT trigger is represented by reactive oxygen species (ROS), which can be generated upon respiratory chain uncoupling. Production of mitochondrial ROS can trigger the NALP3 inflammasome via an unknown mechanism. In some settings, ROS-mediated MPT may favor the release of mitochondrial DNA (mtDNA), which can activate stimulate pro-inflammatory signaling via RIG-I and MDA5, both of which function as viral RNA sensors and interact with mitochondria through the adaptor MAVS. Activated RIG-I and MDA5 promote the activation of NF- κB and interferon regulatory factors (IRFs).

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