Limits...
Zonated induction of autophagy and mitochondrial spheroids limits acetaminophen-induced necrosis in the liver.

Ni HM, Williams JA, Jaeschke H, Ding WX - Redox Biol (2013)

Bottom Line: It is well known that APAP induces mitochondrial damage to trigger centrilobular necrosis.In this graphic review, we discuss the role of autophagy/mitophagy in limiting the expansion of necrosis and promoting mitochondrial biogenesis and liver regeneration for the recovery of APAP-induced liver injury.We also discuss possible mechanisms that could be involved in regulating APAP-induced autophagy/mitophagy and the formation of mitochondrial spheroids.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas 66160, United States.

ABSTRACT
Acetaminophen (APAP) overdose is the most frequent cause of acute liver failure in the US and many western countries. It is well known that APAP induces mitochondrial damage to trigger centrilobular necrosis. Emerging evidence suggests that autophagic removal of damaged mitochondria may protect against APAP-induced liver injury. Electron and confocal microscopy analysis of liver tissues revealed that APAP overdose triggers unique biochemical and pathological zonated changes in the mouse liver, which includes necrosis (zone 1), mitochondrial spheroid formation (zone 2), autophagy (zone 3) and mitochondrial biogenesis (zone 4). In this graphic review, we discuss the role of autophagy/mitophagy in limiting the expansion of necrosis and promoting mitochondrial biogenesis and liver regeneration for the recovery of APAP-induced liver injury. We also discuss possible mechanisms that could be involved in regulating APAP-induced autophagy/mitophagy and the formation of mitochondrial spheroids.

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Parkin negatively regulates mitochondrial spheroid formation. Following mitochondria damage by APAP, mitochondria are depolarized and Parkin is translocated to the outer membrane of mitochondria. In most cases, Parkin promotes Mfn1 and Mfn2 (Mfn1/2) degradation resulting in mitochondrial fragmentation, and Parkin also promotes canonical selective mitophagy through mitochondrial ubiquitination. APAP increases production of nitric oxide (NO) and reactive nitrogen species in certain areas of the liver (such as Zone 2), which may lead to the s-nitrosylation/or other possible translational modifications and inactivation of Parkin to allow Mfn1/2 mediated formation of mitochondrial spheroids. The mitochondrial spheroid pathway could be a default pathway that serves as another alternative mechanism to regulate mitochondrial homeostasis when Parkin is inactivated. Mitochondrial spheroids can contain some lysosomal markers and are acidic and may undergo self-turnover and in turn protect against APAP-induced necrosis.
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f0020: Parkin negatively regulates mitochondrial spheroid formation. Following mitochondria damage by APAP, mitochondria are depolarized and Parkin is translocated to the outer membrane of mitochondria. In most cases, Parkin promotes Mfn1 and Mfn2 (Mfn1/2) degradation resulting in mitochondrial fragmentation, and Parkin also promotes canonical selective mitophagy through mitochondrial ubiquitination. APAP increases production of nitric oxide (NO) and reactive nitrogen species in certain areas of the liver (such as Zone 2), which may lead to the s-nitrosylation/or other possible translational modifications and inactivation of Parkin to allow Mfn1/2 mediated formation of mitochondrial spheroids. The mitochondrial spheroid pathway could be a default pathway that serves as another alternative mechanism to regulate mitochondrial homeostasis when Parkin is inactivated. Mitochondrial spheroids can contain some lysosomal markers and are acidic and may undergo self-turnover and in turn protect against APAP-induced necrosis.

Mentions: How is mitochondrial spheroid formation regulated? Mitochondria are dynamic organelles that constantly undergo fission and fusion. Fission is regulated by the dynamin-related protein 1 (Drp1), fission protein 1 (Fis1) and mitochondrial protein 18 kDa (MTP18). Drp1 does not have any transmembrane domains and requires interaction with Fis1, a protein anchored to the outer membrane of mitochondria. It has been suggested that Drp1 and Fis1 mainly regulate the outer mitochondrial membrane fission while MTP18 regulates the inner mitochondrial membrane fission [58,59]. Mitochondrial fusion is mainly regulated by mitofusin 1 (Mfn1), Mfn2 and optic atrophy 1 (OPA1), where Mfn1 and Mfn2 regulate the outer mitochondrial membrane fusion and OPA1 regulates the inner membrane fusion [60]. Once Parkin is translocated to mitochondria, it promotes the ubiquitination of Mfn1 and Mfn2 and their proteasomal degradation results in mitochondrial fragmentation [21,22]. We found that the formation of mitochondrial spheroids requires either Mfn1 or Mfn2 in cultured cells, and thus Parkin can negatively regulate the formation of mitochondrial spheroids by promoting the degradation of Mfn1 and Mfn2 [28]. Intriguingly, formation of mitochondrial spheroids is still detected in zone 2 next to the necrotic areas (zone 1) in APAP-treated mouse livers that expresses Parkin [61](Fig. 3). Moreover, no obvious changes in Mfn1 and Mfn2 levels were found in APAP-treated mouse livers by western blot analysis even though APAP treatment increased mitochondrial translocation of Parkin (Ding et al., unpublished observations). It is known that the E3 ligase function of Parkin is regulated by post-translational modifications such as phosphorylation, ubiquitination and S-nitrosylation [62]. S-nitrosylation of Parkin inhibits its E3 ligase activity and its protective functions [63]. APAP has been shown to increase levels of nitric oxide and protein nitration in mouse livers, especially in mitochondria [6,64]. Given the gradient and zonation pattern of cytochrome P450 enzymes in the liver, it is likely that the concentrations of NO and reactive nitric species induced by APAP could also display a gradient pattern where it could be enriched in the Zone 2 area next to the necrosis area. Therefore, it is possible that APAP may induce some of these post-translational modifications on Parkin resulting in inactivation of Parkin and formation of mitochondrial spheroids in Zone 2. The possible mechanisms for how APAP induces the formation of mitochondrial spheroids are summarized in Fig. 4. Further work is definitely needed to further elucidate the exact role of post-translational modifications of Parkin induced by APAP in mouse livers. We are currently investigating the role of Parkin-mediated mitophagy in APAP-induced liver injury using the Parkin KO mice.


Zonated induction of autophagy and mitochondrial spheroids limits acetaminophen-induced necrosis in the liver.

Ni HM, Williams JA, Jaeschke H, Ding WX - Redox Biol (2013)

Parkin negatively regulates mitochondrial spheroid formation. Following mitochondria damage by APAP, mitochondria are depolarized and Parkin is translocated to the outer membrane of mitochondria. In most cases, Parkin promotes Mfn1 and Mfn2 (Mfn1/2) degradation resulting in mitochondrial fragmentation, and Parkin also promotes canonical selective mitophagy through mitochondrial ubiquitination. APAP increases production of nitric oxide (NO) and reactive nitrogen species in certain areas of the liver (such as Zone 2), which may lead to the s-nitrosylation/or other possible translational modifications and inactivation of Parkin to allow Mfn1/2 mediated formation of mitochondrial spheroids. The mitochondrial spheroid pathway could be a default pathway that serves as another alternative mechanism to regulate mitochondrial homeostasis when Parkin is inactivated. Mitochondrial spheroids can contain some lysosomal markers and are acidic and may undergo self-turnover and in turn protect against APAP-induced necrosis.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3814950&req=5

f0020: Parkin negatively regulates mitochondrial spheroid formation. Following mitochondria damage by APAP, mitochondria are depolarized and Parkin is translocated to the outer membrane of mitochondria. In most cases, Parkin promotes Mfn1 and Mfn2 (Mfn1/2) degradation resulting in mitochondrial fragmentation, and Parkin also promotes canonical selective mitophagy through mitochondrial ubiquitination. APAP increases production of nitric oxide (NO) and reactive nitrogen species in certain areas of the liver (such as Zone 2), which may lead to the s-nitrosylation/or other possible translational modifications and inactivation of Parkin to allow Mfn1/2 mediated formation of mitochondrial spheroids. The mitochondrial spheroid pathway could be a default pathway that serves as another alternative mechanism to regulate mitochondrial homeostasis when Parkin is inactivated. Mitochondrial spheroids can contain some lysosomal markers and are acidic and may undergo self-turnover and in turn protect against APAP-induced necrosis.
Mentions: How is mitochondrial spheroid formation regulated? Mitochondria are dynamic organelles that constantly undergo fission and fusion. Fission is regulated by the dynamin-related protein 1 (Drp1), fission protein 1 (Fis1) and mitochondrial protein 18 kDa (MTP18). Drp1 does not have any transmembrane domains and requires interaction with Fis1, a protein anchored to the outer membrane of mitochondria. It has been suggested that Drp1 and Fis1 mainly regulate the outer mitochondrial membrane fission while MTP18 regulates the inner mitochondrial membrane fission [58,59]. Mitochondrial fusion is mainly regulated by mitofusin 1 (Mfn1), Mfn2 and optic atrophy 1 (OPA1), where Mfn1 and Mfn2 regulate the outer mitochondrial membrane fusion and OPA1 regulates the inner membrane fusion [60]. Once Parkin is translocated to mitochondria, it promotes the ubiquitination of Mfn1 and Mfn2 and their proteasomal degradation results in mitochondrial fragmentation [21,22]. We found that the formation of mitochondrial spheroids requires either Mfn1 or Mfn2 in cultured cells, and thus Parkin can negatively regulate the formation of mitochondrial spheroids by promoting the degradation of Mfn1 and Mfn2 [28]. Intriguingly, formation of mitochondrial spheroids is still detected in zone 2 next to the necrotic areas (zone 1) in APAP-treated mouse livers that expresses Parkin [61](Fig. 3). Moreover, no obvious changes in Mfn1 and Mfn2 levels were found in APAP-treated mouse livers by western blot analysis even though APAP treatment increased mitochondrial translocation of Parkin (Ding et al., unpublished observations). It is known that the E3 ligase function of Parkin is regulated by post-translational modifications such as phosphorylation, ubiquitination and S-nitrosylation [62]. S-nitrosylation of Parkin inhibits its E3 ligase activity and its protective functions [63]. APAP has been shown to increase levels of nitric oxide and protein nitration in mouse livers, especially in mitochondria [6,64]. Given the gradient and zonation pattern of cytochrome P450 enzymes in the liver, it is likely that the concentrations of NO and reactive nitric species induced by APAP could also display a gradient pattern where it could be enriched in the Zone 2 area next to the necrosis area. Therefore, it is possible that APAP may induce some of these post-translational modifications on Parkin resulting in inactivation of Parkin and formation of mitochondrial spheroids in Zone 2. The possible mechanisms for how APAP induces the formation of mitochondrial spheroids are summarized in Fig. 4. Further work is definitely needed to further elucidate the exact role of post-translational modifications of Parkin induced by APAP in mouse livers. We are currently investigating the role of Parkin-mediated mitophagy in APAP-induced liver injury using the Parkin KO mice.

Bottom Line: It is well known that APAP induces mitochondrial damage to trigger centrilobular necrosis.In this graphic review, we discuss the role of autophagy/mitophagy in limiting the expansion of necrosis and promoting mitochondrial biogenesis and liver regeneration for the recovery of APAP-induced liver injury.We also discuss possible mechanisms that could be involved in regulating APAP-induced autophagy/mitophagy and the formation of mitochondrial spheroids.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas 66160, United States.

ABSTRACT
Acetaminophen (APAP) overdose is the most frequent cause of acute liver failure in the US and many western countries. It is well known that APAP induces mitochondrial damage to trigger centrilobular necrosis. Emerging evidence suggests that autophagic removal of damaged mitochondria may protect against APAP-induced liver injury. Electron and confocal microscopy analysis of liver tissues revealed that APAP overdose triggers unique biochemical and pathological zonated changes in the mouse liver, which includes necrosis (zone 1), mitochondrial spheroid formation (zone 2), autophagy (zone 3) and mitochondrial biogenesis (zone 4). In this graphic review, we discuss the role of autophagy/mitophagy in limiting the expansion of necrosis and promoting mitochondrial biogenesis and liver regeneration for the recovery of APAP-induced liver injury. We also discuss possible mechanisms that could be involved in regulating APAP-induced autophagy/mitophagy and the formation of mitochondrial spheroids.

Show MeSH
Related in: MedlinePlus