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Review
, 2 (2), a009332

Mitochondrial Biology and Parkinson's Disease

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Review

Mitochondrial Biology and Parkinson's Disease

Celine Perier et al. Cold Spring Harb Perspect Med.

Abstract

Mitochondria are highly dynamic organelles with complex structural features which play several important cellular functions, such as the production of energy by oxidative phosphorylation, the regulation of calcium homeostasis, or the control of programmed cell death (PCD). Given its essential role in neuronal viability, alterations in mitochondrial biology can lead to neuron dysfunction and cell death. Defects in mitochondrial respiration have long been implicated in the etiology and pathogenesis of Parkinson's disease (PD). However, the role of mitochondria in PD extends well beyond defective respiration and also involves perturbations in mitochondrial dynamics, leading to alterations in mitochondrial morphology, intracellular trafficking, or quality control. Whether a primary or secondary event, mitochondrial dysfunction holds promise as a potential therapeutic target to halt the progression of dopaminergic neurodegeneration in PD.

Figures

Figure 1.
Figure 1.
Schematic representation of mitochondrial compartmentalization. Mitochondria are divided in four compartments: the outer mitochondrial membrane (OMM), the intermembrane space (IMS), the inner mitochondrial membrane (IMM), and the matrix. The respiratory chain is localized at the IMM whereas the mitochondrial DNA (mtDNA) is located in the matrix. The citric acid cycle (or Krebs cycle or TCA cycle) takes place within the mitochondrial matrix. Asterisk indicates mitochondrial cristae. The respiratory chain, also known as the electron transport chain (ETC) or oxidative phosphorylation system (OXPHOS), is composed of approximately 100 proteins, 13 of which are encoded by the mtDNA. The remaining components are encoded by the nuclear DNA and imported into the mitochondria. It consists of five protein complexes; complex I (NADH dehydrogenase) and complex II (succinate dehydrogenase) receive electrons (e−) from intermediary metabolism, which are then transferred to coenzyme Q and subsequently delivered to complex III (cytochrome c reductase). The electron shuttling protein cytochrome c then transfers the electrons to complex IV (cytochrome c oxidase), which constitutes the final step in the ETC in which molecular oxygen is reduced to water. The electron transport is coupled to proton (H+) pumping across the IMM by complexes I, III, and IV. The resulting proton gradient drives ATP synthesis through complex V (ATP synthase). Reactive oxygen species (ROS), in the form of superoxide (O2), can be generated by the exit of electrons at the level of complex I and III. C, cytochrome c; Q, coenzyme Q. (Images based on Larsson 2010.)
Figure 2.
Figure 2.
Mitochondrial DNA (mtDNA). (A) Mammalian mtDNA is a double-stranded circular molecule containing 37 genes: two ribosomal RNAs (12S and 16S rRNA), 22 transfer RNAs (tRNAs: F, V, L1, I, M, W, D, K, G, R, H, S1, L2, T, P, E, S2, Y, C, N, A, Q), and 13 encoding subunits of the respiratory chain, including seven subunits of complex I (ND1, 2, 3, 4, 4L, 5, and 6), one subunit of complex III (cytochrome b), three subunits of cytochrome c oxidase (COX I, II, and III) and two subunits of ATP synthase (ATP6 and ATP8). (B) In a normal situation, all mtDNAs within a cell are identical (homoplasmy). In a pathological situation linked to pathogenic mtDNA mutations, cells can harbor both normal and mutant mtDNA (heteroplasmy). In the latter case, a minimal number of mutated mtDNAs is required to cause mitochondrial dysfunction and clinical signs (threshold effect). (Images based on Larsson 2010.)
Figure 3.
Figure 3.
Mitochondrial dynamics. (A) Mitochondrial fusion and fission control mitochondrial number and size. Fission is mediated by dynamin-related protein 1 (Drp1) and mitochondrial fission-1 protein (Fis1). Mitofusins (Mnf) 1 and 2 are involved in the fusion of the OMM, whereas protein optic atrophy type 1 (OPA1) regulates the fusion of the IMM. (B) In neurons, mitochondria are recruited to subcellular compartments distant from the cell body, such axons and dendrites, by active transport along microtubules and actin filaments. Distinct molecular motors transport the mitochondria in anterograde or retrograde directions. (C) Selective autophagic degradation of mitochondria (i.e., mitophagy) involves the recruitment of damaged mitochondria into a pre-autophagosome structure via a PINK1/Parkin-dependent process. Targeted mitochondria are then sequestered into double-membrane-bounded autophagosomes and subsequently delivered to lysosomes for degradation.
Figure 4.
Figure 4.
Mitochondrial-dependent apoptosis. Apoptosis can result from the activation of two distinct molecular cascades, known as the extrinsic (or death receptor) and the intrinsic (or mitochondrial) pathways. Both pathways, which can converge at the level of mitochondria, involve the activation of initiator caspases (caspase-8 and -9, respectively) that catalyze the proteolytic maturation of downstream executioner caspases, such as caspase-3, which are the final effectors of cell death. Mitochondrial outer membrane permeabilization (MOMP) represents the point-of-no-return in the mitochondrial apoptotic pathway. Following MOMP, mitochondrial apoptogenic factors such as cytochrome c, Smac/Diablo, endonuclease G, or apoptosis-inducing factor (AIF) are released to the cytosol. Once into the cytosol, these factors can initiate cell death in a caspase-dependent or a caspase-independent manner. Released cytochrome c interacts with two other cytosolic protein factors, Apaf-1 and procaspase-9, to activate caspase-3. Smac/Diablo can interact with several inhibitors of apoptosis (IAPs), thereby relieving the inhibitory effect of IAPs on initiator (e.g., caspase-9) and effector (e.g., caspase-3) caspases. AIF and endonuclease G can translocate to the nucleus and induce caspase-independent DNA fragmentation. MOMP is highly regulated by anti-apoptotic (e.g., Bcl-2 and Bcl-xL) and pro-apoptotic (e.g., Bax and Bak) protein members of the Bcl-2 family. Structurally, all these proteins share up to four Bcl-2-homology domains (BH1–BH4). In addition to multidomain Bcl-2 family members, there are molecules that share sequence homology only with the BH3 domain (such as Bid, Bim, Puma, and Noxa) which can induce cell death either by activating multidomain pro-apoptotic proteins or by inactivating anti-apoptotic proteins. Bid is activated following its cleavage by caspase-8, thus linking the extrinsic and intrinsic pathways at the level of the mitochondria. Whereas several components of the mitochondrial apoptotic pathway have been implicated in the pathogenesis of PD, the participation of the extrinsic pathway in PD has not been consistently shown (Perier et al. 2011). AIF, apoptosis-inducing factor; Casp-9, caspase-9; CL, cardiolipin; OPA1, optic atrophy type 1; Cyt. c, cytochrome c; EndoG, endonuclease G; IAP, inhibitor of apoptosis; tBid, truncated Bid.
Figure 5.
Figure 5.
Mitochondrial dysfunction in PD. Alterations in several aspects of mitochondria biology have been linked to the pathogenesis of PD, such as: (a) reduced complex I activity, (b) increased production of mitochondria-derived ROS, (c) ROS-mediated mtDNA damage, (d) bioenergetic failure, (e) Bax-mediated cytochrome c release and activation of mitochondria-dependent apoptotic pathways, (f) defective mitophagy, or (g) increased mitochondrial Ca2+-buffering burden. Many of the mutated nuclear genes linked to familial forms of PD, including PINK1, Parkin, α-synuclein, DJ-1, or LRRK2, have been shown to affect many of these mitochondrial features (see main text for details). CL, cardiolipin; Cyt. c, cytochrome c; HTRA2, high temperature requirement A2; IMM, inner mitochondrial membrane; IMS, intermembrane space; LRRK2, leucine-rich-repeat kinase 2; OMM, outer mitochondrial membrane PINK1, phosphatase, and tensin homolog-induced kinase 1; ROS, reactive oxygen species; TRAP1, tumor necrosis factor receptor-associated protein 1; α-syn, alpha-synuclein.

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