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Mitophagy and the mitochondrial unfolded protein response in neurodegeneration and bacterial infection.

Pellegrino MW, Haynes CM - BMC Biol. (2015)

Bottom Line: Mitochondria are highly dynamic and structurally complex organelles that provide multiple essential metabolic functions.Mitochondrial dysfunction is associated with neurodegenerative conditions such as Parkinson's disease, as well as bacterial infection.Here, we explore the roles of mitochondrial autophagy (mitophagy) and the mitochondrial unfolded protein response (UPR(mt)) in the response to mitochondrial dysfunction, focusing in particular on recent evidence on the role of mitochondrial import efficiency in the regulation of these stress pathways and how they may interact to protect the mitochondrial pool while initiating an innate immune response to protect against bacterial pathogens.

View Article: PubMed Central - PubMed

ABSTRACT
Mitochondria are highly dynamic and structurally complex organelles that provide multiple essential metabolic functions. Mitochondrial dysfunction is associated with neurodegenerative conditions such as Parkinson's disease, as well as bacterial infection. Here, we explore the roles of mitochondrial autophagy (mitophagy) and the mitochondrial unfolded protein response (UPR(mt)) in the response to mitochondrial dysfunction, focusing in particular on recent evidence on the role of mitochondrial import efficiency in the regulation of these stress pathways and how they may interact to protect the mitochondrial pool while initiating an innate immune response to protect against bacterial pathogens.

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Mitochondrial protein import and PINK1-mediated mitophagy. (A) The vast majority of mitochondrial proteins are encoded by nuclear genes, synthesized on cytosolic ribosomes and targeted to mitochondria via mitochondrial targeting sequences (MTS). To reach the mitochondrial matrix, proteins synthesized on cytosolic ribosomes first interact with the translocase of the outer membrane (TOM) and then with the translocase of the inner membrane (TIM). Crossing the inner membrane requires both complexes, a membrane potential (Ψ) across the inner mitochondrial membrane that is generated by the respiratory chain, ATP and molecular chaperones (CH) within the mitochondrial matrix. Once in the matrix, the MTS is typically cleaved, allowing the protein to fold and assemble appropriately. Perturbations to the TOM/TIM complexes, respiratory chain, membrane potential and mitochondrial chaperones results in reduced mitochondrial import efficiency. (B) The kinase PINK1 serves to monitor mitochondrial health and initiate mitochondrial degradation when an organelle is severely damaged. Normally, PINK1, localized to mitochondria by its MTS sequence, is efficiently imported into the mitochondrion and subsequently degraded. However, when a mitochondrion is damaged (red), resulting in a depleted inner membrane potential or because of high levels of unfolded proteins in the matrix, PINK1 fails to be imported and accumulates on the mitochondrial outer membrane, allowing recognition of the damaged organelle in a sequence of steps, the first of which is the recruitment of the ubiquitin ligase Parkin to the outer mitochondrial membrane. PINK1 phosphorylates ubiquitin (Ub) and the ubiquitin ligase Parkin, and activated Parkin then ubiquitinates outer mitochondrial membrane proteins, leading to the recruitment of the autophagosome machinery and engulfment of the damaged organelle. Precise engulfment requires the Rab GAP TBC1D15 (shown in grey), which is bound to the mitochondrial outer membrane via interaction with LC3/GABARAP (not shown). The autophagosome then fuses with a lysosome, leading to degradation of the defective mitochondria by the proteases and lipases that reside in lysosomes.
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Fig1: Mitochondrial protein import and PINK1-mediated mitophagy. (A) The vast majority of mitochondrial proteins are encoded by nuclear genes, synthesized on cytosolic ribosomes and targeted to mitochondria via mitochondrial targeting sequences (MTS). To reach the mitochondrial matrix, proteins synthesized on cytosolic ribosomes first interact with the translocase of the outer membrane (TOM) and then with the translocase of the inner membrane (TIM). Crossing the inner membrane requires both complexes, a membrane potential (Ψ) across the inner mitochondrial membrane that is generated by the respiratory chain, ATP and molecular chaperones (CH) within the mitochondrial matrix. Once in the matrix, the MTS is typically cleaved, allowing the protein to fold and assemble appropriately. Perturbations to the TOM/TIM complexes, respiratory chain, membrane potential and mitochondrial chaperones results in reduced mitochondrial import efficiency. (B) The kinase PINK1 serves to monitor mitochondrial health and initiate mitochondrial degradation when an organelle is severely damaged. Normally, PINK1, localized to mitochondria by its MTS sequence, is efficiently imported into the mitochondrion and subsequently degraded. However, when a mitochondrion is damaged (red), resulting in a depleted inner membrane potential or because of high levels of unfolded proteins in the matrix, PINK1 fails to be imported and accumulates on the mitochondrial outer membrane, allowing recognition of the damaged organelle in a sequence of steps, the first of which is the recruitment of the ubiquitin ligase Parkin to the outer mitochondrial membrane. PINK1 phosphorylates ubiquitin (Ub) and the ubiquitin ligase Parkin, and activated Parkin then ubiquitinates outer mitochondrial membrane proteins, leading to the recruitment of the autophagosome machinery and engulfment of the damaged organelle. Precise engulfment requires the Rab GAP TBC1D15 (shown in grey), which is bound to the mitochondrial outer membrane via interaction with LC3/GABARAP (not shown). The autophagosome then fuses with a lysosome, leading to degradation of the defective mitochondria by the proteases and lipases that reside in lysosomes.

Mentions: Thirteen essential components of the respiratory chain, and ATP synthase, which catalyzes the final step in the generation of ATP, are encoded by the mitochondrial genome (mtDNA). They are translated on mitochondrial ribosomes and directly inserted into the mitochondrial inner membrane [1]. Mitochondrial proteins encoded in the nucleus and translated on cytosolic ribosomes by contrast must be targeted to the mitochondria and subsequently imported (Figure 1A). In most cases the targeting is achieved by an amino-terminal mitochondrial targeting sequence (MTS), although internal sequences also exist [2]. Once at the mitochondrial outer membrane, the protein is directed to the appropriate mitochondrial subcompartment: the outer membrane, intermembrane space, inner membrane or matrix. To enter the matrix, the protein crosses the inner membrane through the TIM (translocase of inner membrane) complex, where the MTS is cleaved and the protein folds and assembles into its functional conformation. Crossing the inner membrane requires both a membrane potential, which is generated by a functional respiratory chain, and molecular chaperones located in the mitochondrial matrix (Figure 1A). Mitochondrial protein import is disrupted in multiple pathologic states, and is emerging as a central regulatory step affecting metabolism and stress responses [3].Figure 1


Mitophagy and the mitochondrial unfolded protein response in neurodegeneration and bacterial infection.

Pellegrino MW, Haynes CM - BMC Biol. (2015)

Mitochondrial protein import and PINK1-mediated mitophagy. (A) The vast majority of mitochondrial proteins are encoded by nuclear genes, synthesized on cytosolic ribosomes and targeted to mitochondria via mitochondrial targeting sequences (MTS). To reach the mitochondrial matrix, proteins synthesized on cytosolic ribosomes first interact with the translocase of the outer membrane (TOM) and then with the translocase of the inner membrane (TIM). Crossing the inner membrane requires both complexes, a membrane potential (Ψ) across the inner mitochondrial membrane that is generated by the respiratory chain, ATP and molecular chaperones (CH) within the mitochondrial matrix. Once in the matrix, the MTS is typically cleaved, allowing the protein to fold and assemble appropriately. Perturbations to the TOM/TIM complexes, respiratory chain, membrane potential and mitochondrial chaperones results in reduced mitochondrial import efficiency. (B) The kinase PINK1 serves to monitor mitochondrial health and initiate mitochondrial degradation when an organelle is severely damaged. Normally, PINK1, localized to mitochondria by its MTS sequence, is efficiently imported into the mitochondrion and subsequently degraded. However, when a mitochondrion is damaged (red), resulting in a depleted inner membrane potential or because of high levels of unfolded proteins in the matrix, PINK1 fails to be imported and accumulates on the mitochondrial outer membrane, allowing recognition of the damaged organelle in a sequence of steps, the first of which is the recruitment of the ubiquitin ligase Parkin to the outer mitochondrial membrane. PINK1 phosphorylates ubiquitin (Ub) and the ubiquitin ligase Parkin, and activated Parkin then ubiquitinates outer mitochondrial membrane proteins, leading to the recruitment of the autophagosome machinery and engulfment of the damaged organelle. Precise engulfment requires the Rab GAP TBC1D15 (shown in grey), which is bound to the mitochondrial outer membrane via interaction with LC3/GABARAP (not shown). The autophagosome then fuses with a lysosome, leading to degradation of the defective mitochondria by the proteases and lipases that reside in lysosomes.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4384303&req=5

Fig1: Mitochondrial protein import and PINK1-mediated mitophagy. (A) The vast majority of mitochondrial proteins are encoded by nuclear genes, synthesized on cytosolic ribosomes and targeted to mitochondria via mitochondrial targeting sequences (MTS). To reach the mitochondrial matrix, proteins synthesized on cytosolic ribosomes first interact with the translocase of the outer membrane (TOM) and then with the translocase of the inner membrane (TIM). Crossing the inner membrane requires both complexes, a membrane potential (Ψ) across the inner mitochondrial membrane that is generated by the respiratory chain, ATP and molecular chaperones (CH) within the mitochondrial matrix. Once in the matrix, the MTS is typically cleaved, allowing the protein to fold and assemble appropriately. Perturbations to the TOM/TIM complexes, respiratory chain, membrane potential and mitochondrial chaperones results in reduced mitochondrial import efficiency. (B) The kinase PINK1 serves to monitor mitochondrial health and initiate mitochondrial degradation when an organelle is severely damaged. Normally, PINK1, localized to mitochondria by its MTS sequence, is efficiently imported into the mitochondrion and subsequently degraded. However, when a mitochondrion is damaged (red), resulting in a depleted inner membrane potential or because of high levels of unfolded proteins in the matrix, PINK1 fails to be imported and accumulates on the mitochondrial outer membrane, allowing recognition of the damaged organelle in a sequence of steps, the first of which is the recruitment of the ubiquitin ligase Parkin to the outer mitochondrial membrane. PINK1 phosphorylates ubiquitin (Ub) and the ubiquitin ligase Parkin, and activated Parkin then ubiquitinates outer mitochondrial membrane proteins, leading to the recruitment of the autophagosome machinery and engulfment of the damaged organelle. Precise engulfment requires the Rab GAP TBC1D15 (shown in grey), which is bound to the mitochondrial outer membrane via interaction with LC3/GABARAP (not shown). The autophagosome then fuses with a lysosome, leading to degradation of the defective mitochondria by the proteases and lipases that reside in lysosomes.
Mentions: Thirteen essential components of the respiratory chain, and ATP synthase, which catalyzes the final step in the generation of ATP, are encoded by the mitochondrial genome (mtDNA). They are translated on mitochondrial ribosomes and directly inserted into the mitochondrial inner membrane [1]. Mitochondrial proteins encoded in the nucleus and translated on cytosolic ribosomes by contrast must be targeted to the mitochondria and subsequently imported (Figure 1A). In most cases the targeting is achieved by an amino-terminal mitochondrial targeting sequence (MTS), although internal sequences also exist [2]. Once at the mitochondrial outer membrane, the protein is directed to the appropriate mitochondrial subcompartment: the outer membrane, intermembrane space, inner membrane or matrix. To enter the matrix, the protein crosses the inner membrane through the TIM (translocase of inner membrane) complex, where the MTS is cleaved and the protein folds and assembles into its functional conformation. Crossing the inner membrane requires both a membrane potential, which is generated by a functional respiratory chain, and molecular chaperones located in the mitochondrial matrix (Figure 1A). Mitochondrial protein import is disrupted in multiple pathologic states, and is emerging as a central regulatory step affecting metabolism and stress responses [3].Figure 1

Bottom Line: Mitochondria are highly dynamic and structurally complex organelles that provide multiple essential metabolic functions.Mitochondrial dysfunction is associated with neurodegenerative conditions such as Parkinson's disease, as well as bacterial infection.Here, we explore the roles of mitochondrial autophagy (mitophagy) and the mitochondrial unfolded protein response (UPR(mt)) in the response to mitochondrial dysfunction, focusing in particular on recent evidence on the role of mitochondrial import efficiency in the regulation of these stress pathways and how they may interact to protect the mitochondrial pool while initiating an innate immune response to protect against bacterial pathogens.

View Article: PubMed Central - PubMed

ABSTRACT
Mitochondria are highly dynamic and structurally complex organelles that provide multiple essential metabolic functions. Mitochondrial dysfunction is associated with neurodegenerative conditions such as Parkinson's disease, as well as bacterial infection. Here, we explore the roles of mitochondrial autophagy (mitophagy) and the mitochondrial unfolded protein response (UPR(mt)) in the response to mitochondrial dysfunction, focusing in particular on recent evidence on the role of mitochondrial import efficiency in the regulation of these stress pathways and how they may interact to protect the mitochondrial pool while initiating an innate immune response to protect against bacterial pathogens.

Show MeSH
Related in: MedlinePlus