Mitophagy Selectively Degrades Individual Damaged Mitochondria After Photoirradiation

ArticleinAntioxidants & Redox Signaling 14(10):1919-28 · December 2010with29 Reads
DOI: 10.1089/ars.2010.3768 · Source: PubMed
Damaged and dysfunctional mitochondria are proposed to be removed by autophagy. However, selective degradation of damaged mitochondria by autophagy (mitophagy) has yet to be experimentally verified. In this study, we investigated the cellular fate of individual mitochondria damaged by photoirradiation in hepatocytes isolated from transgenic mice expressing green fluorescent protein fused to microtubule-associated protein 1 light chain 3, a marker of forming and newly formed autophagosomes. Photoirradiation with 488-nm light induced mitochondrial depolarization (release of tetramethylrhodamine methylester [TMRM]) in a dose-dependent fashion. At lower doses of light, mitochondria depolarized transiently with re-polarization within 3 min. With greater light, mitochondrial depolarization became irreversible. Irreversible, but not reversible, photodamage induced autophagosome formation after 32±5 min. Photodamage-induced mitophagy was independent of TMRM, as photodamage also induced mitophagy in the absence of TMRM. Photoirradiation with 543-nm light did not induce mitophagy. As revealed by uptake of LysoTracker Red, mitochondria weakly acidified after photodamage before a much stronger acidification after autophagosome formation. Photodamage-induced mitophagy was not blocked by phosphatidylinositol 3-kinase inhibition with 3-methyladenine (10 mM) or wortmannin (100 nM). In conclusion, individual damaged mitochondria become selectively degraded by mitophagy, but photodamage-induced mitophagic sequestration occurs independently of the phosphatidylinositol 3-kinase signaling pathway, the classical upstream signaling pathway of nutrient deprivation-induced autophagy.
    • "For details see Burté et al. (2015). Selective mitochondrial mitophagy removes damaged mitochondria and closely associated to biogenesis, which permits replacement of mitochondria and assembly of multiple mitochondrial proteins (Kim and Lemasters, 2011). Thus, maintenance of protein homeostasis through MQC is one of the key aspects in preservation of functional integrity of neuronal mitochondria (Bohovych et al., 2016). "
    Full-text · Article · Sep 2016
    • "The view that autophagic processes can remove damaged and dysfunctional mitochondria was directly confirmed by experiments in which selected mitochondria inside living hepatocytes were subjected to laser-induced photodamage [202]. Mitochondrial depolarization and inner membrane permeabilization seemed to be required for autophagy signal- ing [202] suggesting involvement of MPT pore opening and swelling in the mitophagy. A growing body of evidence now suggests that processes of autophagy and/or apoptosis involving other cellular organelles are able to protect tissues in conditions leading to oxidative stress. "
    [Show abstract] [Hide abstract] ABSTRACT: There is significant evidence that, in living systems, free radicals and other reactive oxygen and nitrogen species play a double role, because they can cause oxidative damage and tissue dysfunction and serve as molecular signals activating stress responses that are beneficial to the organism. Mitochondria have been thought to both play a major role in tissue oxidative damage and dysfunction and provide protection against excessive tissue dysfunction through several mechanisms, including stimulation of opening of permeability transition pores. Until recently, the functional significance of ROS sources different from mitochondria has received lesser attention. However, the most recent data, besides confirming the mitochondrial role in tissue oxidative stress and protection, show interplay between mitochondria and other ROS cellular sources, so that activation of one can lead to activation of other sources. Thus, it is currently accepted that in various conditions all cellular sources of ROS provide significant contribution to processes that oxidatively damage tissues and assure their survival, through mechanisms such as autophagy and apoptosis.
    Full-text · Article · Jul 2016
    • "This radiation induced mitochondrial dysfunction and biogenesis has been shown to be associated with mitophagy induction[75]. Photo-irradiation of individual mitochondria from primary hepatocytes causes altered mitochondrial potential, inner membrane permeablization, excessive ROS generation, and mitophagy induction in a dose-dependent manner and phosphatidylinositol 3-kinase-independent manner[75]. Mitophagy shows a strong correlation with metabolic reprogramming in irradiated cancer cells[76]. "
    [Show abstract] [Hide abstract] ABSTRACT: Autophagy is an evolutionary conserved, indispensable, lysosome-mediated degradation process, which helps in maintaining homeostasis during various cellular traumas. During stress, a context-dependent role of autophagy has been observed which drives the cell towards survival or death depending upon the type, time, and extent of the damage. The process of autophagy is stimulated during various cellular insults, e.g. oxidative stress, endoplasmic reticulum stress, imbalances in calcium homeostasis, and altered mitochondrial potential. Ionizing radiation causes ROS-dependent as well as ROS-independent damage in cells that involve macromolecular (mainly DNA) damage, as well as ER stress induction, both capable of inducing autophagy. This review summarizes the current understanding on the roles of oxidative stress, ER stress, DNA damage, altered mitochondrial potential, and calcium imbalance in radiation-induced autophagy as well as the merits and limitations of targeting autophagy as an approach for radioprotection and radiosensitization.
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