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. 2022 May:64:1-18.
doi: 10.1016/j.mito.2022.02.004. Epub 2022 Feb 16.

Site-specific mitochondrial dysfunction in neurodegeneration

Anežka Vodičková  1 , Shon A Koren  2 , Andrew P Wojtovich  3
Affiliations

Site-specific mitochondrial dysfunction in neurodegeneration

Anežka Vodičková et al. Mitochondrion. 2022 May.

Abstract

Mitochondria are essential for neuronal survival and mitochondrial dysfunction is a hallmark of neurodegeneration. The loss in mitochondrial energy production, oxidative stress, and changes in calcium handling are associated with neurodegenerative diseases; however, different sites and types of mitochondrial dysfunction are linked to distinct neuropathologies. Understanding the causal or correlative relationship between changes in mitochondria and neuropathology will lead to new therapeutic strategies. Here, we summarize the evidence of site-specific mitochondrial dysfunction and mitochondrial-related clinical trials for neurodegenerative diseases. We further discuss potential therapeutic approaches, such as mitochondrial transplantation, restoration of mitochondrial function, and pharmacological alleviation of mitochondrial dysfunction.

Keywords: Mitochondria-targeting therapeutics; Mitochondrial dysfunction; Neurodegeneration; Optogenetics; Transplantation.

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Conflict of interest statement

Declarations of interest: None

Figures

Fig. 1
Fig. 1. The mitochondrial electron transport chain and oxidative phosphorylation.
The electron transport chain (ETC) is comprised of protein complexes that transfer electrons from reducing equivalents to oxygen, ultimately generating a protonmotive force (pmf). More specifically, electrons enter complex I or complex II and are passed to coenzyme Q. Complex III then transfers electrons from coenzyme Q to cytochrome c. Finally, electrons are transferred from cytochrome c to molecular oxygen by complex IV, resulting in water. Throughout the process, protons are pumped from the matrix to the intermembrane space generating the pmf, which is composed of a chemical and electrical gradient. ATP synthase utilizes the pmf to produce ATP by shuttling protons back into the matrix. Together, these complexes couple the movement of electrons and protons to generate electrical and chemical gradients that fuel ATP production. Protein shapes are derived from RCSB protein data bank (PDB) structures. Complex I (6ZR2), complex II (1ZOY), complex III (1L0N), complex IV (1OCC), complex V (5ARA), cyt c – cytochrome c, IMM – inner mitochondrial membrane, IMS – intermembrane space, Q – ubiquinone, TCA cycle – tricarboxylic acid cycle.
Fig. 2
Fig. 2. Schematic representation of site-specific neuronal mitochondrial dysfunction in Parkinson’s disease.
Mitochondrial dysfunction in Parkinson’s disease is represented by a blue-colored shapes with an arrow indicating increased or decreased activity or amount. The proteins represented in the figure include the proteins mentioned in this text, but further detailed review articles are referred to in relevant sections. Where available, protein shapes are derived from RCSB protein data bank (PDB) structures. CHCHD2 - Coiled-Coil-Helix-Coiled-Coil-Helix Domain Containing protein 2, complex I – NADH dehydrogenase (6ZR2), complex II – succinate dehydrogenase (1ZOY), complex III - cytochrome c reductase (1L0N), complex IV – cytochrome c oxidase (1OCC), complex V – ATP synthase (5ARA), cyt c – cytochrome c, DJ-1 – Parkinson’s disease protein 7 (3BWE), ER – endoplasmic reticulum, IMM – inner mitochondrial membrane, IMMT – Mic60/mitofilin, IMS – intermembrane space, LRRK2 – leucine rich repeat kinase 2 (6XAF), MAMs – mitochondria-associated ER membranes, Mfn2 – mitofusin 2 (6JFN), Miro (6D71), NCLX – mitochondrial sodium calcium exchanger (3V5U), OMM – outer mitochondrial membrane, OPA1 – optic atrophy protein 1 (6JTG), Parkin (5C9V), PINK1 - PTEN-induced kinase 1 (5OAT), Q – ubiquinone, RHOT2 - mitochondrial Rho GTPase 2, ROS – reactive oxygen species, TCA cycle – tricarboxylic acid cycle, Tom20 (1OM2), Tom22 (7CK6).
Fig. 3
Fig. 3. Schematic representation of site-specific neuronal mitochondrial dysfunction in Alzheimer’s disease.
Mitochondrial dysfunction in Alzheimer’s disease is represented by a blue-colored shapes with an arrow indicating increased or decreased activity or amount. The proteins represented in the figure include the proteins mentioned in this text, but further detailed review articles are referred to in relevant sections. Where available, protein shapes are derived from RCSB protein data bank (PDB) structures. Complex I – NADH dehydrogenase (6ZR2), complex II – succinate dehydrogenase (1ZOY), complex III – cytochrome c reductase (1L0N), complex IV – cytochrome c oxidase (1OCC), complex V – ATP synthase (5ARA), cyt c – cytochrome c, Drp1 –dynamin-related protein 1 (4H1U), Fis1 – mitochondrial fission 1 protein (1PC2), IMM – inner mitochondrial membrane, IMS – intermembrane space, KGDHC – alpha-ketoglutarate dehydrogenase complex (2JGD), Mfn1 – mitofusin 1 (5GNS), Mfn2 – mitofusin 2 (6JFN), NCLX – mitochondrial sodium calcium exchanger (3V5U), OMM – outer mitochondrial membrane, OPA1 – optic atrophy protein 1 (6JTG), PDHC – pyruvate dehydrogenase complex (6CFO), Q – ubiquinone, ROS – reactive oxygen species, TCA cycle – tricarboxylic acid cycle, Tom20 (1OM2), Tom70 (2GW1).
Fig. 4
Fig. 4. Schematic representation of site-specific neuronal mitochondrial dysfunction in Huntington’s disease.
Mitochondrial dysfunction in Huntington’s disease is represented by a blue-colored shapes with an arrow indicating increased or decreased activity or amount. The proteins represented in the figure include the proteins mentioned in this text, but further detailed review articles are referred to in relevant sections. Where available, protein shapes are derived from RCSB protein data bank (PDB) structures. Complex I – NADH dehydrogenase (6ZR2), complex II – succinate dehydrogenase (1ZOY), complex III – cytochrome c reductase (1L0N), complex IV – cytochrome c oxidase (1OCC), complex V – ATP synthase (5ARA), cyt c – cytochrome c, Drp1 –dynamin-related protein 1 (4H1U), IMM – inner mitochondrial membrane, IMS – intermembrane space, OMM – outer mitochondrial membrane, Q – ubiquinone, ROS – reactive oxygen species, TCA cycle – tricarboxylic acid cycle
Fig. 5
Fig. 5. Schematic representation of site-specific neuronal mitochondrial dysfunction in ALS-FTD spectrum.
Mitochondrial dysfunction in ALS-FTD spectrum is represented by a blue-colored shapes with an arrow indicating increased or decreased activity or amount. The proteins represented in the figure include the proteins mentioned in this text, but further detailed review articles are referred to in relevant sections. Where available, protein shapes are derived from RCSB protein data bank (PDB) structures. CHCHD10 – Coiled-Coil-Helix-Coiled-Coil-Helix Domain Containing protein 10, complex I – NADH dehydrogenase (6ZR2), complex II – succinate dehydrogenase (1ZOY), complex III – cytochrome c reductase (1L0N), complex IV – cytochrome c oxidase (1OCC), complex V – ATP synthase (5ARA), cyt c – cytochrome c, IMM – inner mitochondrial membrane, IMS – intermembrane space, OMM – outer mitochondrial membrane, Q – ubiquinone, ROS – reactive oxygen species, SOD1 – superoxide dismutase 1 (2APS, is usually present in the cytosol, but can also occur in the IMS), TCA cycle – tricarboxylic acid cycle, VDAC – voltage-dependent anion channel (2K4T).
Fig. 6
Fig. 6. Graphical overview of therapeutic approaches to address mitochondrial dysfunction in neurodegenerative diseases.
Genetic or environmental challenges can result in increased reactive oxygen species production and decreased mitochondrial activity. Mitochondrial dysfunction can further act as a feed-forward cycle causing energetic failure and cellular dysfunction, which are hallmarks of neurodegenerative disease. Multiple approaches to treat mitochondrial dysfunction include transplanting/transferring healthy mitochondria into the damaged tissue or increasing the biogenesis of new undamaged mitochondria. Other approaches can reprogram metabolism to overcome barriers imposed by dysfunctional metabolic machinery or use small molecules to target outcomes of dysfunction. ETC – respiratory chain, ROS – reactive oxygen species.
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