Buscar este blog

domingo, 13 de febrero de 2011

Neurodegeneración y mitocondrias

The Failure of Mitochondria Leads to Neurodegeneration: Do Mitochondria Need A Jump Start?

Junghee Leea,b, Jung Hyun Booc, and Hoon Ryua,b,*
aDepartment of Neurology, Boston University School of Medicine, Boston, MA 02118
bVeterans Affairs Boston Healthcare System, Boston, MA 02130, USA
cDepartment of Biomedical Sciences, Seoul National University College of Medicine, Seoul,
Republic of Korea


Mitochondria are the power engine generating biochemical energy in the cell. Mitochondrial dysfunction and bioenergy deficiency is closely linked to the pathogenesis of neurodegenerative disorders. Mitochondria play a variety of roles by integrating extracellular signals and executing important intracellular events in neuronal survival and death. In this context, the regulation of mitochondrial function via therapeutic approaches may exert some salutary and neuroprotective mechanisms. Understanding the relationship of mitochondria-dependent pathogenesis may provide important pharmacological utility in the treatment of neurodegenerative conditions such as Alzheimer’s disease, amyotrophic lateral sclerosis, Huntington’s disease and Parkinson’s disease. Indeed, the modulation of mitochondrial pathways is rapidly emerging as a novel therapeutic target.
This review focuses on how mitochondria are involved in neurodegeneration and what therapeutics are available to target mitochondrial pathways.

Neuroprotection; Alzheimer’s disease; Amyotrophic lateral sclerosis; Huntington’s disease;
Parkinson’s disease; Therapeutics

Figure 1. Mitochondria-dependent mechanisms of neurodegeneration and potential therapeutic targets
A growing body of evidence from in vitro and in vivo studies has implicated Aβ, mutant SOD1 (mSOD1), mutant huntingtin (mHTT), mutant a-synuclein and their ability to induce mitochondrial dysfunction as being toxic to neurons. Aβ-mediated mitochondrial stress through an interaction with cyclophilin D (CypD). The binding of excessive Aβ to heme causes oxidative damage to macromolecules and leads to mitochondrial dysfunction and neurotoxicity. Mitochondria dysfunction and oxidative stress is closely linked to mutation of SOD1. The dysfunction of mitochondrial oxidative phosphorylation is implicated in the pathogenesis of ALS. The neurotoxins 3-NP and MPTP disrupt mitochondrial function and result in idiopathic HD and PD. The neurodegenerative and multiple pathogenic molecules interact with mitochondrial molecules and lead to mitochondrial dysfunction, oxidative stress, and apoptosis of neurons. In this paradigm, the relative pathogenicity of Aβ, mSOD1, mHTT, and mutant α-synuclein is dependent on their mitochondrial interacting molecules and pathways. Omi/HtrA2 has emerged to play a role in protein quality control in AD, HD and PD
and its mutation is linked to motor neuronal degeneration in ALS.

Figure 2. Therapeutic targeting of mitochondria-dependent neuropathogenic mechanisms Nicotinamide, carnitine, resveratrol, and Sirtuins modulate tricarboxylic acid (TCA) cycle in mitochondria. Desferoxamine may trigger mitochondrial protein kinase A (PKA) activity and mitochondrial CREB-mediated transcription. The antioxidant and bioenergetic compounds creatine, β-hydroxybutyrate, and coenzyme Q10 can improve mitochondrial function by preventing 3-nitropropionic acid (3-NP)-induced cytotoxicity, while cyclosporine A, FK 506, melatonine, and Dimebon influence mitochondrial membrane function and inhibit cytochrome c release and mitochondrial permeability transition pore (mtPTP)-induced cytotoxicity. Rosiglitazone promotes maintenance of mitochondrial Ca2+ activity. Specific estrogen receptor modulators (SERMs) also affect the mitochondrial activity by modulating calcium fluxes and may activate transcription of mitochondrial genes by interacting with mitochondrial ERs. Cloquinol regulates the mitochondrial oxidative phosphorylation pathway via demethoxyubiquinone hydroxylase (CLK-1 gene product) that catalyzes the production of coenzyme Q. The reversible inhibitor of caspase activity reduces pro-apoptotic signaling in the mitochondria. In addition, compounds exhibiting a robust antioxidant effect lead to the improvement of mitochondrial oxidative metabolism, bioenergy production, and neuronal survival.
Lee et al. Page 17
Adv Drug Deliv Rev. Author manuscript; available in PMC 2010 November 30.


No hay comentarios: