Limits...
Morphological and bioenergetic demands underlying the mitophagy in post-mitotic neurons: the pink-parkin pathway.

Amadoro G, Corsetti V, Florenzano F, Atlante A, Bobba A, Nicolin V, Nori SL, Calissano P - Front Aging Neurosci (2014)

Bottom Line: Evidence suggests a striking causal relationship between changes in quality control of neuronal mitochondria and numerous devastating human neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis.Contrary to replicating mammalian cells with a metabolism essentially glycolytic, post-mitotic neurons are distinctive owing to (i) their exclusive energetic dependence from mitochondrial metabolism and (ii) their polarized shape, which entails compartmentalized and distinct energetic needs.Here, we review the recent findings on mitochondrial dynamics and mitophagy in differentiated neurons focusing on how the exceptional characteristics of neuronal populations in their morphology and bioenergetics needs make them quite different to other cells in controlling the intracellular turnover of these organelles.

View Article: PubMed Central - PubMed

Affiliation: Institute of Translational Pharmacology - National Research Council Rome, Italy ; European Brain Research Institute Rome, Italy.

ABSTRACT
Evidence suggests a striking causal relationship between changes in quality control of neuronal mitochondria and numerous devastating human neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis. Contrary to replicating mammalian cells with a metabolism essentially glycolytic, post-mitotic neurons are distinctive owing to (i) their exclusive energetic dependence from mitochondrial metabolism and (ii) their polarized shape, which entails compartmentalized and distinct energetic needs. Here, we review the recent findings on mitochondrial dynamics and mitophagy in differentiated neurons focusing on how the exceptional characteristics of neuronal populations in their morphology and bioenergetics needs make them quite different to other cells in controlling the intracellular turnover of these organelles.

No MeSH data available.


Related in: MedlinePlus

Cartoon illustrating steps in the mitochondrial clearance mediated by the Pink1–Parkin pathway. (A) In physiological conditions, Pink-1 is constitutively imported into healthy mitochondria via TIM/TOM complex to the inner membrane (IMM), cleaved by presenilin-associated rhomboid-like protease (PARL), and then proteolytically degraded. (B) Upon ΔΨ collapse, full-length Pink1 is not processed accumulating at the outer membrane (OMM) to recruit Parkin onto depolarized mitochondria. PINK1 autophosphorylation at Ser228 and Ser402 (P) is essential for efficient mitochondrial localization of Parkin. The PINK1-dependent Parkin phos-phorylation at Ser65, combined with unknown factor(s) (?), is required not only for its efficient translocation but also for the degradation of mito-chondrial proteins during mitophagy. (C) After being recruited on OMM, Parkin triggers mitophagy by ubiquitylating (Ub, K48, K63) several proteins including Mfns1/2, VDAC, TOM. Proteasome-mediated removal of Mfns1/2 not only inhibits mitochondrial fusion but also prevents its default rear-raggedright rangement into spheroids, allowing thus the damaged organelles to be recognized by the engulfing autophagosome. Cytosolic autophagy adaptor p62 (also known as sequestosome 1, SQSTM1) is also involved in mito-phagy as its K63-ubiquitin-binding domain (UBA) as well as an LC3- binding domain (LIR), recruits autophagosomes to ubiquitylated protein. For more information on Pink–Parkin-dependent mitophagy, please refer to recent excellent reviews (Twig and Shirihai, 2011; Vives-Bauza and Przedborski, 2011; Youle and Narendra, 2011; Ding and Yin, 2012; Jin and Youle, 2012). Freely adapted from Figure 6 of (Okatsu et al., 2012).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3927396&req=5

Figure 3: Cartoon illustrating steps in the mitochondrial clearance mediated by the Pink1–Parkin pathway. (A) In physiological conditions, Pink-1 is constitutively imported into healthy mitochondria via TIM/TOM complex to the inner membrane (IMM), cleaved by presenilin-associated rhomboid-like protease (PARL), and then proteolytically degraded. (B) Upon ΔΨ collapse, full-length Pink1 is not processed accumulating at the outer membrane (OMM) to recruit Parkin onto depolarized mitochondria. PINK1 autophosphorylation at Ser228 and Ser402 (P) is essential for efficient mitochondrial localization of Parkin. The PINK1-dependent Parkin phos-phorylation at Ser65, combined with unknown factor(s) (?), is required not only for its efficient translocation but also for the degradation of mito-chondrial proteins during mitophagy. (C) After being recruited on OMM, Parkin triggers mitophagy by ubiquitylating (Ub, K48, K63) several proteins including Mfns1/2, VDAC, TOM. Proteasome-mediated removal of Mfns1/2 not only inhibits mitochondrial fusion but also prevents its default rear-raggedright rangement into spheroids, allowing thus the damaged organelles to be recognized by the engulfing autophagosome. Cytosolic autophagy adaptor p62 (also known as sequestosome 1, SQSTM1) is also involved in mito-phagy as its K63-ubiquitin-binding domain (UBA) as well as an LC3- binding domain (LIR), recruits autophagosomes to ubiquitylated protein. For more information on Pink–Parkin-dependent mitophagy, please refer to recent excellent reviews (Twig and Shirihai, 2011; Vives-Bauza and Przedborski, 2011; Youle and Narendra, 2011; Ding and Yin, 2012; Jin and Youle, 2012). Freely adapted from Figure 6 of (Okatsu et al., 2012).

Mentions: The Pink/Parkin pathway involves the interplay of two recessive Parkinson’s-linked genes PTEN-induced kinase 1 (PINK1) – a mitochondrially targeted serine/threonine kinase – and Parkin – an E3 ubiquitin ligase – which cooperate in maintaining the mitochondrial integrity by regulating several physiological processes of these organelles, including their membrane potential, calcium homeostasis, cristae structure, respiratory activity, and mtDNA integrity (Trempe and Fon, 2013). In addition, the Pink/Parkin pathway is crucial for autophagy-dependent clearance of dysfunctional mitochondria (Narendra et al., 2008; Matsuda et al., 2010; Figure 3) as, in the absence of PINK1 or Parkin, cells often develop fragmented mitochondria (Büeler, 2010). Specifically, in mammalian cells, cytosolic Parkin is selectively recruited to dysfunctional, depolarized mitochondria upon dissipation of ΔΨm by chemical uncoupler CCCP (carbonyl cyanide m-chlorophenyl hydrazone), then promoting their autophagic-lysosomal-mediated degradation. The Parkin translocation to depolarized mitochondria requires the activity of PINK which – in basal conditions – constantly undergoes a ΔΨm-dependent import into these organelles followed by specific maturation mediated by intrinsic protease(s), including matrix metalloproteinase (MMP), presenilin-associated-rhomboid-like (PARL), matrix-oriented AAA protease (m-AAA), and caseinolytic peptidase XP (ClpXP). Conversely, in response to low potential, full-length PINK is not imported/cleaved but rapidly stabilized, accumulating thus on outer membrane TOM (translocase of the outer membrane) complex (Batlevi and La Spada, 2011; Ashrafi and Schwarz, 2013; Grenier et al., 2013) where it engages Parkin which, in turn, triggers the mitochondria deliver toward autophagic-lysosomal pathway. Pink indeed recruits, directly or indirectly, Parkin from cytosol in close proximity on depolarized mitochondria and critically promotes its E3 ubiquitin ligase activity, likely by Ser65-phosphorylation, in the initial step of mitophagy (Kondapalli et al., 2012; Shiba-Fukushima et al., 2012; Iguchi et al., 2013). Parkin recruitment to mitochondria induces ubiquitination of several targets such as mitochondrial fusion proteins mitofusins (Mfns1/2) and voltage-dependent-activated channel (VDAC; Gegg et al., 2010; Geisler et al., 2010) whose proteasomal degradation (Chan et al., 2011; Yoshii et al., 2011) provokes the fragmentation of the organelle followed by its engulfment by autophagosomes (Deas et al., 2011). In addition p97, an AAA+ATPase, also accumulates on mitochondria in a Parkin-dependent manner to promote the degradation of OMM proteins and then mitophagy (Tanaka et al., 2010). Concerning the role of Parkin-mediated ubiquitination of Mfns1/2 in promoting mitophagy, two different but not mutually exclusive models have been proposed. To start with, the degradation of Mfns1/2 by UPS might disperse the clustered mitochondria and facilitate their engulfment by autophagosomes (Chan et al., 2011). Secondly, the removal of this pro-fusion mitochondrial protein shifts the balance toward the fragmentation – which is crucial in triggering mitophagy (Twig et al., 2008) – likely by physically interfering with the formation of Mfns1/2 trans-homodimers needed for tethering of these organelles (Ziviani and Whitworth, 2010). Alternatively, Parkin-mediated degradation might remove several negative regulators localized on the mitochondrial surface, thereby unmasking a molecular signal for recruitment of depolarized mitochondria by autophagosomes (Chan et al., 2011). Interestingly, the Parkin-induced elimination of Mfns1/2 is necessary for mitophagy to occur as it prevents the activation of an inhibitory default pathway in which depolarized and fragmented mitochondria undergo a drastic conformational change to become large spheroids that are not recognized by autophagosomes (Ding et al., 2012).


Morphological and bioenergetic demands underlying the mitophagy in post-mitotic neurons: the pink-parkin pathway.

Amadoro G, Corsetti V, Florenzano F, Atlante A, Bobba A, Nicolin V, Nori SL, Calissano P - Front Aging Neurosci (2014)

Cartoon illustrating steps in the mitochondrial clearance mediated by the Pink1–Parkin pathway. (A) In physiological conditions, Pink-1 is constitutively imported into healthy mitochondria via TIM/TOM complex to the inner membrane (IMM), cleaved by presenilin-associated rhomboid-like protease (PARL), and then proteolytically degraded. (B) Upon ΔΨ collapse, full-length Pink1 is not processed accumulating at the outer membrane (OMM) to recruit Parkin onto depolarized mitochondria. PINK1 autophosphorylation at Ser228 and Ser402 (P) is essential for efficient mitochondrial localization of Parkin. The PINK1-dependent Parkin phos-phorylation at Ser65, combined with unknown factor(s) (?), is required not only for its efficient translocation but also for the degradation of mito-chondrial proteins during mitophagy. (C) After being recruited on OMM, Parkin triggers mitophagy by ubiquitylating (Ub, K48, K63) several proteins including Mfns1/2, VDAC, TOM. Proteasome-mediated removal of Mfns1/2 not only inhibits mitochondrial fusion but also prevents its default rear-raggedright rangement into spheroids, allowing thus the damaged organelles to be recognized by the engulfing autophagosome. Cytosolic autophagy adaptor p62 (also known as sequestosome 1, SQSTM1) is also involved in mito-phagy as its K63-ubiquitin-binding domain (UBA) as well as an LC3- binding domain (LIR), recruits autophagosomes to ubiquitylated protein. For more information on Pink–Parkin-dependent mitophagy, please refer to recent excellent reviews (Twig and Shirihai, 2011; Vives-Bauza and Przedborski, 2011; Youle and Narendra, 2011; Ding and Yin, 2012; Jin and Youle, 2012). Freely adapted from Figure 6 of (Okatsu et al., 2012).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3927396&req=5

Figure 3: Cartoon illustrating steps in the mitochondrial clearance mediated by the Pink1–Parkin pathway. (A) In physiological conditions, Pink-1 is constitutively imported into healthy mitochondria via TIM/TOM complex to the inner membrane (IMM), cleaved by presenilin-associated rhomboid-like protease (PARL), and then proteolytically degraded. (B) Upon ΔΨ collapse, full-length Pink1 is not processed accumulating at the outer membrane (OMM) to recruit Parkin onto depolarized mitochondria. PINK1 autophosphorylation at Ser228 and Ser402 (P) is essential for efficient mitochondrial localization of Parkin. The PINK1-dependent Parkin phos-phorylation at Ser65, combined with unknown factor(s) (?), is required not only for its efficient translocation but also for the degradation of mito-chondrial proteins during mitophagy. (C) After being recruited on OMM, Parkin triggers mitophagy by ubiquitylating (Ub, K48, K63) several proteins including Mfns1/2, VDAC, TOM. Proteasome-mediated removal of Mfns1/2 not only inhibits mitochondrial fusion but also prevents its default rear-raggedright rangement into spheroids, allowing thus the damaged organelles to be recognized by the engulfing autophagosome. Cytosolic autophagy adaptor p62 (also known as sequestosome 1, SQSTM1) is also involved in mito-phagy as its K63-ubiquitin-binding domain (UBA) as well as an LC3- binding domain (LIR), recruits autophagosomes to ubiquitylated protein. For more information on Pink–Parkin-dependent mitophagy, please refer to recent excellent reviews (Twig and Shirihai, 2011; Vives-Bauza and Przedborski, 2011; Youle and Narendra, 2011; Ding and Yin, 2012; Jin and Youle, 2012). Freely adapted from Figure 6 of (Okatsu et al., 2012).
Mentions: The Pink/Parkin pathway involves the interplay of two recessive Parkinson’s-linked genes PTEN-induced kinase 1 (PINK1) – a mitochondrially targeted serine/threonine kinase – and Parkin – an E3 ubiquitin ligase – which cooperate in maintaining the mitochondrial integrity by regulating several physiological processes of these organelles, including their membrane potential, calcium homeostasis, cristae structure, respiratory activity, and mtDNA integrity (Trempe and Fon, 2013). In addition, the Pink/Parkin pathway is crucial for autophagy-dependent clearance of dysfunctional mitochondria (Narendra et al., 2008; Matsuda et al., 2010; Figure 3) as, in the absence of PINK1 or Parkin, cells often develop fragmented mitochondria (Büeler, 2010). Specifically, in mammalian cells, cytosolic Parkin is selectively recruited to dysfunctional, depolarized mitochondria upon dissipation of ΔΨm by chemical uncoupler CCCP (carbonyl cyanide m-chlorophenyl hydrazone), then promoting their autophagic-lysosomal-mediated degradation. The Parkin translocation to depolarized mitochondria requires the activity of PINK which – in basal conditions – constantly undergoes a ΔΨm-dependent import into these organelles followed by specific maturation mediated by intrinsic protease(s), including matrix metalloproteinase (MMP), presenilin-associated-rhomboid-like (PARL), matrix-oriented AAA protease (m-AAA), and caseinolytic peptidase XP (ClpXP). Conversely, in response to low potential, full-length PINK is not imported/cleaved but rapidly stabilized, accumulating thus on outer membrane TOM (translocase of the outer membrane) complex (Batlevi and La Spada, 2011; Ashrafi and Schwarz, 2013; Grenier et al., 2013) where it engages Parkin which, in turn, triggers the mitochondria deliver toward autophagic-lysosomal pathway. Pink indeed recruits, directly or indirectly, Parkin from cytosol in close proximity on depolarized mitochondria and critically promotes its E3 ubiquitin ligase activity, likely by Ser65-phosphorylation, in the initial step of mitophagy (Kondapalli et al., 2012; Shiba-Fukushima et al., 2012; Iguchi et al., 2013). Parkin recruitment to mitochondria induces ubiquitination of several targets such as mitochondrial fusion proteins mitofusins (Mfns1/2) and voltage-dependent-activated channel (VDAC; Gegg et al., 2010; Geisler et al., 2010) whose proteasomal degradation (Chan et al., 2011; Yoshii et al., 2011) provokes the fragmentation of the organelle followed by its engulfment by autophagosomes (Deas et al., 2011). In addition p97, an AAA+ATPase, also accumulates on mitochondria in a Parkin-dependent manner to promote the degradation of OMM proteins and then mitophagy (Tanaka et al., 2010). Concerning the role of Parkin-mediated ubiquitination of Mfns1/2 in promoting mitophagy, two different but not mutually exclusive models have been proposed. To start with, the degradation of Mfns1/2 by UPS might disperse the clustered mitochondria and facilitate their engulfment by autophagosomes (Chan et al., 2011). Secondly, the removal of this pro-fusion mitochondrial protein shifts the balance toward the fragmentation – which is crucial in triggering mitophagy (Twig et al., 2008) – likely by physically interfering with the formation of Mfns1/2 trans-homodimers needed for tethering of these organelles (Ziviani and Whitworth, 2010). Alternatively, Parkin-mediated degradation might remove several negative regulators localized on the mitochondrial surface, thereby unmasking a molecular signal for recruitment of depolarized mitochondria by autophagosomes (Chan et al., 2011). Interestingly, the Parkin-induced elimination of Mfns1/2 is necessary for mitophagy to occur as it prevents the activation of an inhibitory default pathway in which depolarized and fragmented mitochondria undergo a drastic conformational change to become large spheroids that are not recognized by autophagosomes (Ding et al., 2012).

Bottom Line: Evidence suggests a striking causal relationship between changes in quality control of neuronal mitochondria and numerous devastating human neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis.Contrary to replicating mammalian cells with a metabolism essentially glycolytic, post-mitotic neurons are distinctive owing to (i) their exclusive energetic dependence from mitochondrial metabolism and (ii) their polarized shape, which entails compartmentalized and distinct energetic needs.Here, we review the recent findings on mitochondrial dynamics and mitophagy in differentiated neurons focusing on how the exceptional characteristics of neuronal populations in their morphology and bioenergetics needs make them quite different to other cells in controlling the intracellular turnover of these organelles.

View Article: PubMed Central - PubMed

Affiliation: Institute of Translational Pharmacology - National Research Council Rome, Italy ; European Brain Research Institute Rome, Italy.

ABSTRACT
Evidence suggests a striking causal relationship between changes in quality control of neuronal mitochondria and numerous devastating human neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis. Contrary to replicating mammalian cells with a metabolism essentially glycolytic, post-mitotic neurons are distinctive owing to (i) their exclusive energetic dependence from mitochondrial metabolism and (ii) their polarized shape, which entails compartmentalized and distinct energetic needs. Here, we review the recent findings on mitochondrial dynamics and mitophagy in differentiated neurons focusing on how the exceptional characteristics of neuronal populations in their morphology and bioenergetics needs make them quite different to other cells in controlling the intracellular turnover of these organelles.

No MeSH data available.


Related in: MedlinePlus