title: In aging, the vulnerability of rat brain mitochondria is enhanced due to reduced level of 2',3'-cyclic nucleotide-3'-phosphodiesterase (CNP) and subsequently increased permeability transition in brain mitochondria in old animals.
abstract: Aging is accompanied by progressive dysfunction of mitochondria associated with a continuous decrease of their capacity to produce ATP. Mitochondria isolated from brain of aged animals show an increased mitochondrial permeability transition pore (mPTP) opening. We recently detected new regulators of mPTP function in brain mitochondria, the enzyme 2', 3'-cyclic nucleotide 3'-phosphodiesterase (CNP) and its substrates 2', 3'-cAMP and 2', 3'-cNADP, and the neuronal protein p42(IP4). Here, we compared parameters of mPTP opening in non-synaptic brain mitochondria isolated from young and old rats. In mitochondria from old rats (>18 months), mPTP opening occurred at a lower threshold of Ca(2+) concentration than in mitochondria from young rats (<3 months). mPTP opening in mitochondria from old rats was accelerated by 2', 3'-cAMP, which further lowered the threshold Ca(2+) concentration. In non-synaptic mitochondria from old rats, the CNP level was decreased by 34%. Lowering of the CNP level in non-synaptic mitochondria with aging was accompanied by decreased levels of voltage-dependent anion channel (VDAC; by 69%) and of p42(IP4) (by 59%). Thus, reduced levels of CNP in mitochondria could lead to a rise in the concentration of the mPTP promoter 2', 3'-cAMP. The level of CNP and p42(IP4) and, probably VDAC, might be essential for myelination and electrical activity of axons. We propose that in aging the reduction in the level of these proteins leads to mitochondrial dysfunction, in particular, to a decreased threshold Ca(2+) concentration to induce mPTP opening. This might represent initial steps of age-related mitochondrial dysfunction, resulting in myelin and axonal pathology.
authors.affiliation: Institute of Theoretical and Experimental Biophysics, Russian Academy of Science, Pushchino, Moscow region, Russia; Institut für Neurobiochemie, Otto-von-Guericke-Universität Magdeburg, Medizinische Fakultät, Magdeburg, Germany.
authors.forename: Olga
authors.initials: O
authors.lastname: Krestinina
authors.affiliation: Institute of Theoretical and Experimental Biophysics, Russian Academy of Science, Pushchino, Moscow region, Russia; Institut für Neurobiochemie, Otto-von-Guericke-Universität Magdeburg, Medizinische Fakultät, Magdeburg, Germany.
authors.forename: Tamara
authors.initials: T
authors.lastname: Azarashvili
authors.affiliation: Institute of Theoretical and Experimental Biophysics, Russian Academy of Science, Pushchino, Moscow region, Russia; Institut für Neurobiochemie, Otto-von-Guericke-Universität Magdeburg, Medizinische Fakultät, Magdeburg, Germany.
authors.forename: Yulia
authors.initials: Y
authors.lastname: Baburina
authors.affiliation: Institut für Neurobiochemie, Otto-von-Guericke-Universität Magdeburg, Medizinische Fakultät, Magdeburg, Germany.
authors.forename: Anastasia
authors.initials: A
authors.lastname: Galvita
authors.affiliation: Institute of Theoretical and Experimental Biophysics, Russian Academy of Science, Pushchino, Moscow region, Russia; Institut für Neurobiochemie, Otto-von-Guericke-Universität Magdeburg, Medizinische Fakultät, Magdeburg, Germany.
authors.forename: Dmitry
authors.initials: D
authors.lastname: Grachev
authors.affiliation: Institut für Neurobiochemie, Otto-von-Guericke-Universität Magdeburg, Medizinische Fakultät, Magdeburg, Germany.
authors.forename: Rolf
authors.initials: R
authors.lastname: Stricker
authors.affiliation: Institut für Neurobiochemie, Otto-von-Guericke-Universität Magdeburg, Medizinische Fakultät, Magdeburg, Germany. Electronic address: georg.reiser@med.ovgu.de.
authors.forename: Georg
authors.initials: G
authors.lastname: Reiser
mesh_terms: D063309:2',3'-Cyclic Nucleotide 3'-Phosphodiesterase / Q000378:metabolism*; D000375:Aging / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism*; D008297:Male; D008928:Mitochondria / Q000378:metabolism*; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism*; D000083162:Mitochondrial Permeability Transition Pore; D051381:Rats; D017208:Rats, Wistar
chemical_list: D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D063309:2',3'-Cyclic Nucleotide 3'-Phosphodiesterase; C571339:Cnp protein, rat
keywords: 2′,3′-cyclic nucleotide 3′-phosphodiesterase; Age-dependent changes; Aging; Rat brain mitochondria (RBM); mPTP