Figure 2.

The biphasic mitochondrial model in bipolar disorders. Left: Depression mitochondrial model—Decreased mitochondrial biogenesis. Changes during depressive phases include mitochondrial DNA damage (including mutations and polymorphisms), membrane permeability, and increased formation of ROS. These imbalances lead to a pro-inflammatory state, with increased levels of pro-inflammatory cytokines (IL-1, IL-6 and TNFα) and decreased antioxidant enzymes (glutathione, SOD and catalase). These disturbances can cause cytotoxicity, increased apoptosis, and dampened synaptic plasticity and neuronal differentiation. Antidepressant drugs have shown the capacity to restore mitochondrial disregulation by reestablishing the oxidant/antioxidant balance and counteract the negative effects of depression on the mitochondria. Right: Mania mitochondrial model—Increased mitochondrial biogenesis. Upward arrows symbolize an increase. Changes during manic phases include increased inflammation and elevated production of ROS and RNS, driven by increased activity of the NF-kB signaling pathway. NF-kB signaling stimulates mitochondrial biogenesis via the upregulation of PGC-1α, Nrf-2, and TFAM. PGC-1α and Nrf-2 stimulate mitochondrial respiration, which is a further source of oxidative stress via ROS and RNS production. Increased oxidative stress could induce an increase in the levels of cytosolic Ca²⁺ ions seen in mania compared to other phases of the disease. Elevated Ca²⁺ levels can stimulate oxidative phosphorylation and ATP production and may lead to the activation of AMPK and SIRT1, which may increase the activity of NAD+. In an environment of increasing oxidative stress, the activity of SIRT1, AMPK, PKC PI3/K are increased. This can foster mitochondrial survival leading to cytotoxicity and cell death via activation of proapoptotic pathway cascades (Bcl-2, Akt and mTor among others). Increased uric acid levels increase the uptake of Ca²⁺ ions by mitochondria, increase the mitochondrial membrane potential and therefore enhance ATP production. Antimanic drugs including mood stabilizers and antipsychotics may restore mitochondrial dysregulation by counteracting the mitochondrial imbalance leading to neurogenesis, neuroplasticity, and cell survival. ADP, adenosine diphosphate; ATP, adenosine triphosphate; BDNF, brain-derived neurotrophic factor; C, complex; Cyt c, cytochrome c; e-, electron; ECT, electron transport chain; FAD, flavin adenine dinucleotide; IL, Interleukin; Q, coenzyme Q; mt DNA, mitochondrial DNA; mTOR, mechanistic target of rapamycin; NAD, nicotinamide adenine dinucleotide; NF, nuclear factor; Pi, inorganic phosphate; PI3/K, Inositol 1,4,5 triphosphate; PKC, Protein Kinase C; ROS, reactive oxygen species; RNS, reactive nitrogen species; TFAM, mitochondrial transcription factor A; TNFα, tumor necrosis factor-alpha.