Mitochondrial dysfunction in bipolar disorder: evidence from magnetic resonance spectroscopy research

Abstract

Magnetic resonance spectroscopy (MRS) affords a noninvasive window on in vivo brain chemistry and, as such, provides a unique opportunity to gain insight into the biochemical pathology of bipolar disorder. Studies utilizing proton ( 1 H) MRS have identified changes in cerebral concentrations of N-acetyl aspartate, glutamate/glutamine, choline-containing compounds, myo-inositol, and lactate in bipolar subjects compared to normal controls, while studies using phosphorus ( 31 P) MRS have examined additional alterations in levels of phosphocreatine, phosphomonoesters, and intracellular pH. We hypothesize that the majority of MRS findings in bipolar subjects can be fit into a more cohesive bioenergetic and neurochemical model of bipolar illness that is both novel and yet in concordance with findings from complementary methodological approaches. In this review, we propose a hypothesis of mitochondrial dysfunction in bipolar disorder that involves impaired oxidative phosphorylation, a resultant shift toward glycolytic energy production, a decrease in total energy production and/or substrate availability, and altered phospholipid metabolism. Molecular Psychiatry (2005) 10, 900-919.

Neural circuitry and neuroplasticity in mood disorders: Insights for novel therapeutic targets

“…Studies using proton ( 1 H) MRS have identified changes in cerebral concentrations of N-acetyl aspartate (NAA), glutamate/glutamine (Glx), cholinecontaining compounds, myo-inositol (mI), and lactate in bipolar subjects compared with normal controls. 148 Studies using phosphorus ( 31 P) MRS have examined additional alterations in levels of phosphocreatine (PCr), phosphomonoesters (PMEs), and intracellular pH (pHi). 149 These seemingly disparate findings of increased lactate and GLX, decreased NAA, and decreased pHi in bipolar subjects suggest a shift away from oxidative phosphorylation toward glycolysis, leading to reduced total energy output and efficiency (reviewed in Stork and Renshaw 2005).…”

“…148 Studies using phosphorus ( 31 P) MRS have examined additional alterations in levels of phosphocreatine (PCr), phosphomonoesters (PMEs), and intracellular pH (pHi). 149 These seemingly disparate findings of increased lactate and GLX, decreased NAA, and decreased pHi in bipolar subjects suggest a shift away from oxidative phosphorylation toward glycolysis, leading to reduced total energy output and efficiency (reviewed in Stork and Renshaw 2005). 148 Mitochondria play a critical role in maintaining calcium homeostasis.…”

“…149 These seemingly disparate findings of increased lactate and GLX, decreased NAA, and decreased pHi in bipolar subjects suggest a shift away from oxidative phosphorylation toward glycolysis, leading to reduced total energy output and efficiency (reviewed in Stork and Renshaw 2005). 148 Mitochondria play a critical role in maintaining calcium homeostasis. Excessive levels of calcium are a critical mediator of cell death cascades within neurons, necessitating homeostatic mechanisms to regulate intracellular calcium levels precisely.…”

Increased Anterior Cingulate/Medial Prefrontal Cortical Glutamate and Creatine in Bipolar Depression

“…As reviewed elsewhere (Moore and Galloway, 2002;Stork and Renshaw, 2005;Stanley, 2002;Strakowski, 2005), resonances in the 1 HMR spectrum can be reliably quantified for several metabolites with brain concentrations in the millimolar range including N-acetyl-aspartate (NAA), a marker of neuronal viability; the excitatory amino-acid glutamate (Glu); glutamine (Gln), the glial cell reservoir storage form of glutamate; the sum of Glu and Gln (Glx); creatine + phosphocreatine (Cr), a measure of energy utilization which, given its relative stability, has historically been used as an 1 HMRS internal standard; choline related compounds (Cho) including glycerophosphocholine, phosphocholine, and acetylcholine some of which are involved in membrane metabolism; and myo-inositol (mI), a component of the cellular phosphoinositol-cycle second-messenger system.…”

Relationship altered between functional T1ρ and BOLD signals in bipolar disorder

“…fT1ρ mapping is of particular interest to study in bipolar disorder because the illness has been associated with metabolic abnormalities, in particular mitochondrial dysfunction (Clay, Sillivan, & Konradi, 2011; Kato, 2007; Stork & Renshaw, 2005). MR spectroscopy studies have shown that baseline pH is reduced (i.e., more acidic) in the anterior cingulate in people with bipolar disorder in the euthymic state compared to normal controls (Kato, Kunugi, Nanko, & Kato, 2000; Kato et al., 1998).…”