An analysis of the effects of Mn2+ on oxidative phosphorylation in liver, brain, and heart mitochondria using state 3 oxidation rate assays

Abstract

Manganese (Mn) toxicity is partially mediated by reduced ATP production. We have used oxidation rate assays -a measure of ATP production -under rapid phosphorylation conditions to explore sites of Mn 2+ inhibition of ATP production in isolated liver, brain, and heart mitochondria. This approach has several advantages. First, the target tissue for Mn toxicity in the basal ganglia is energetically active and should be studied under rapid phosphorylation conditions. Second, Mn may inhibit metabolic steps which don't affect ATP production rate. This approach allows identification of inhibitions that decrease this rate. Third, mitochondria from different tissues contain different amounts of the components of the metabolic pathways potentially resulting in different patterns of ATP inhibition. Our results indicate that Mn 2+ inhibits ATP production with very different patterns in liver, brain, and heart mitochondria. The primary Mn 2+ inhibition site in liver and heart mitochondria, but not in brain mitochondria, is the F 1 F 0 ATP synthase. In mitochondria fueled by either succinate or glutamate + malate, ATP production is much more strongly inhibited in brain than in liver or heart mitochondria; moreover, Mn 2+ inhibits two independent sites in brain mitochondria. The primary site of Mn-induced inhibition of ATP production in brain mitochondria when succinate is substrate is either fumarase or complex II,

Differential interaction of hGDH1 and hGDH2 with manganese: Implications for metabolism and toxicity

“…Given the differential distribution of the two isoenzymes , this could result in differential vulnerability of different tissues to Mn. This is also consistent with the fact that mitochondrial function is differentially affected by Mn in various tissues (Gunter et al, 2010).…”

Y 3+ , La 3+ , and some bivalent metals inhibited the opening of the Tl + -induced permeability transition pore in Ca 2+ -loaded rat liver mitochondria

“…It was earlier found that the inhibition of MPTP by Sr 2+ and Mn 2+ resulted in interaction of these metal ions with Ca 2+ sites facing the matrix [4,5,7,8,38,43]. However, bivalent metal ions such as Sr 2+ [14,26,50], Ni 2+ [30], Ba 2+ [13], Mn 2+ [9,15,28], as well as RR [43,62,66] can decrease the release of Ca 2+ from the mitochondrial matrix. The mitochondrial K + /H + antiporter was inhibited by these metal ions in a lot of Mn 2+ b Ca 2+ b Mg 2+ b Sr 2+ ( [67] and reference inside).…”

“…It is known that Ca 2+ [8,9] as well as Sr 2+ , Ba 2+ , and Mn 2+ [10][11][12][13][14][15][16] but not Ni 2+ [17] or La 3+ [18][19][20] are transported in the matrix via the mitochondrial calcium uniporter (MCU). The influence of these cations on mitochondrial Ca 2+ uptake depends on their ionic crystal radii [20,21] and hydration enthalpy [22].…”

Manganese accumulation in the CNS and associated pathologies

“…Parkinsonism and dystonia are common as sequelae of Mn, cyanide and carbon monoxide (CO) intoxications (Borgohain et al 1995;Calne et al 1994;Carella et al 1988;Choi 1983;Lee and Marsden 1994). Why Mn is able to produce the same effects that those substances is not known but there may be common mechanisms of injury; for example all of them are able to produce alterations in oxidative phosphorylation (Gunter et al 2010;Iheagwara et al 2007;Leavesley et al 2010) and both Mn and CO induce mPT and ROS production (Piantadosi et al 2006;Rao and Norenberg 2004).…”