Mitochondrial metabolism is a highly orchestrated phenomenon in which many enzyme systems cooperate in a variety of pathways to dictate cellular fate. As well as its vital role in cellular energy metabolism (ATP production), mitochondria are powerful organelles that regulate reactive oxygen species production, NAD+/NADH ratio and programmed cell death. In addition, mitochondrial abnormalities have been well recognized to contribute to degenerative diseases, like Parkinson's disease (PD). Particularly a deficiency in the mitochondrial respiratory chain complex I and cristae disruption have been consistently described in PD. Moreover, the products of PD-familial genes, including alpha-synuclein, Parkin, PINK1, DJ-1, LRRK2 and HTR2A, were shown to localize to the mitochondria under certain conditions. It seems that PD has a mitochondrial component so events that would modulate normal mitochondrial functions may compromise neuronal survival. However, it remains an open question whether alterations of these pathways lead to different aspects of PD or whether they converge at a point that is the common denominator of PD pathogenesis. In this review we will focus on mitochondrial metabolic control and its implications on sirtuins activation, microtubule dynamics and autophagic-lysosomal pathway. We will address mitochondrial metabolism modulation as a new promising therapeutic tool for PD.
"Moreover, defects in axonal and dendritic transport have also been linked to various neurodegenerative processes, including sPD pathogenesis. Indeed, sPD is characterized by a sequence of neuropathological events that arise due to a dying-back pattern of neuronal degeneration, namely early loss of synaptic terminals and axonopathy, before cell death    . Another central hallmark of PD is the presence of intracytoplasmatic aggregates, named Lewy Bodies that are mainly composed of alpha-synuclein (ASYN). "
[Show abstract][Hide abstract] ABSTRACT: In Parkinson's disease mitochondrial dysfunction can lead to a deficient ATP supply to microtubule protein motors leading to mitochondrial axonal transport disruption. Compromised axonal transport will then lead to a disorganized distribution of mitochondria and other organelles in the cell, as well as, the accumulation of aggregated proteins like alpha-synuclein. Moreover, axonal transport disruption can trigger synaptic accumulation of autophagosomes packed with damaged mitochondria and protein aggregates promoting synaptic failure. We previously observed that neuronal-like cells with an inherent mitochondrial impairment derived from PD patients contain a disorganized microtubule network, as well as, alpha-synuclein oligomers accumulation. In this work we provide new evidence that an agent that promotes microtubule network assembly, NAP (davunetide), improves microtubule-dependent traffic, restores the autophagic flux and potentiates autophasosome-lysosome fusion leading to autophagic vacuole clearance in Parkinson's disease cells. Moreover, NAP is capable of efficiently reduce alpha-synuclein oligomer content and its sequestration by the mitochondria. Most interestingly, NAP decreases mitochondrial ubiquitination levels, as well as, increases mitochondrial membrane potential indicating a rescue in mitochondrial function. Overall, we demonstrate that by improving microtubule-mediated traffic, we can avoid mitochondrial-induced damage and thus recover cell homeostasis. These results prove that NAP may be a promising therapeutic lead candidate for neurodegenerative diseases that involve axonal transport failure and mitochondrial impairment as hallmarks, like Parkinson's disease and related disorders.
"Proteomic approaches have been used to identify MPTP-induced changes in the expression of multiple proteins associated with defective energy metabolism, ubiquitin proteasome system, apoptosis and mitochondrial function . A few proteins, which decide the fate of the genetic forms of PD, are localized in or interact with the mitochondria and mitochondrial dysfunction could affect neuronal survival . MPTP and maneb and paraquat have been shown to affect the mitochondrial protein complexes, their effects on the proteins of the mitochondrion and the roles of such proteins in the mechanisms of neurodegeneration have not been fully characterized. "
[Show abstract][Hide abstract] ABSTRACT: Mitochondrial dysfunction is the foremost perpetrator of the nigrostriatal dopaminergic neurodegeneration leading to Parkinson's disease (PD). However, the roles played by majority of the mitochondrial proteins in PD pathogenesis have not yet been deciphered. Present study investigated the effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and combined maneb and paraquat on the mitochondrial proteome of the nigrostriatal tissues in the presence or absence of minocycline, levodopa and manganese (III) tetrakis (1-methyl-4-pyridyl) porphyrin (MnTMPyP). The differentially expressed proteins were identified and proteome profiles were correlated with the pathological and biochemical anomalies induced by MPTP and maneb and paraquat. MPTP altered the expression of twelve while combined maneb and paraquat altered the expression of fourteen proteins. Minocycline, levodopa and MnTMPyP, respectively, restored the expression of three, seven and eight proteins in MPTP and seven, eight and eight proteins in maneb- and paraquat-treated groups. Although levodopa and MnTMPyP rescued from MPTP- and maneb- and paraquat-mediated increase in the microglial activation and decrease in Mn-SOD expression and complex I activity, dopamine content and number of dopaminergic neurons, minocycline defended mainly against maneb- and paraquat-mediated alterations. The results demonstrate that MPTP and combined maneb and paraquat induce mitochondrial dysfunction and microglial activation and alter the expression of a bunch of mitochondrial proteins leading to the nigrostriatal dopaminergic neurodegeneration and minocycline, levodopa or MnTMPyP variably offset scores of such changes.
Biochimica et Biophysica Acta 04/2013; DOI:10.1016/j.bbadis.2013.03.019 · 4.66 Impact Factor
"In this revised theory, a progressive cellular aging occurs due to accumulating oxidative damage to mitochondria and failure of cellular bioenergetic processes. Mitochondrial dysfunction is associated with the pathogenesis of several neurodegenerative diseases, including AD for (refs see Moreira et al., 2010a) and PD (for refs see Arduino et al., 2010). Mitochondrial dysfunction plays a critical role in the pathologic mechanisms of neurologic disorders or diseases associated with the aging process (Beal, 2005; Morais and De Strooper, 2010; Moreira et al., 2010b; Nicholls, 2009; Soane et al., 2007). "
[Show abstract][Hide abstract] ABSTRACT: Aging and neurodegenerative conditions such as Alzheimer and Parkinson diseases are characterized by tissue and mitochondrial changes that compromise brain function. Alterations can include increased reactive oxygen species production and impaired antioxidant capacity with a consequent increase in oxidative damage, mitochondrial dysfunction that compromises brain ATP production, and ultimately increased apoptotic signaling and neuronal death. Among several non-pharmacological strategies to prevent brain degeneration, physical exercise is a surprisingly effective strategy, which antagonizes brain tissue and mitochondrial dysfunction. The present review aims to discuss the role of physical exercise in the modulation of the mechanisms involved in neuroprotection including the activation of signaling pathways underlying brain protection.
Progress in Neurobiology 08/2012; 99(2):149-62. DOI:10.1016/j.pneurobio.2012.08.002 · 9.99 Impact Factor
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