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Review
. 2017 Jan 15;482(3):388-398.
doi: 10.1016/j.bbrc.2016.10.126. Epub 2017 Feb 3.

Redox dynamics of manganese as a mitochondrial life-death switch

Matthew Ryan Smith  1 , Jolyn Fernandes  1 , Young-Mi Go  1 , Dean P Jones  2
Affiliations
Review

Redox dynamics of manganese as a mitochondrial life-death switch

Matthew Ryan Smith et al. Biochem Biophys Res Commun. .

Abstract

Sten Orrenius, M.D., Ph.D., pioneered many areas of cellular and molecular toxicology and made seminal contributions to our knowledge of oxidative stress and glutathione (GSH) metabolism, organellar functions and Ca+2-dependent mechanisms of cell death, and mechanisms of apoptosis. On the occasion of his 80th birthday, we summarize current knowledge on redox biology of manganese (Mn) and its role in mechanisms of cell death. Mn is found in all organisms and has critical roles in cell survival and death mechanisms by regulating Mn-containing enzymes such as manganese superoxide dismutase (SOD2) or affecting expression and activity of caspases. Occupational exposures to Mn cause "manganism", a Parkinson's disease-like condition of neurotoxicity, and experimental studies show that Mn exposure leads to accumulation of Mn in the brain, especially in mitochondria, and neuronal cell death occurs with features of an apoptotic mechanism. Interesting questions are why a ubiquitous metal that is essential for mitochondrial function would accumulate to excessive levels, cause increased H2O2 production and lead to cell death. Is this due to the interactions of Mn with other essential metals, such as iron, or with toxic metals, such as cadmium? Why is the Mn loading in the human brain so variable, and why is there such a narrow window between dietary adequacy and toxicity? Are non-neuronal tissues similarly vulnerable to insufficiency and excess, yet not characterized? We conclude that Mn is an important component of the redox interface between an organism and its environment and warrants detailed studies to understand the role of Mn as a mitochondrial life-death switch.

Keywords: Heavy metal; Hydrogen peroxide; MnSOD; Neurodegenerative disease; Nutritional metal; Redox state.

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Figures

Fig. 1
Fig. 1
Manganese is similar to iron due to comparable electron shells and atomic radii. Elemental manganese has 13 electrons in the 3rd orbital (A, orange) in comparison to Fe which has 14 (B, dark orange). Both Mn and Fe share 2 electrons (e− ) in the 4s orbital (black). Comparing the different oxidation state of electron configurations between Fe and Mn, in Fe+2 both electrons in the 4s orbital are lost, however there remains a paired set of electrons in the 3d orbital. Pairing of other 3d electrons can occur in the presence of strong field ligands (B, Fe+2). Fe+3 ions (B, Fe+3) share the same number of electrons as Mn+2 (A, Mn+2) with 5 unpaired elections in the 3d orbital compared to Mn+3 which has 4 unpaired electrons in the 3d orbital (A, Mn+3). In addition, comparing the atomic and ionic radii of Mn (A, bottom) and Fe (B, bottom) also shows similarity in the size of the orbitals using 6-coordinate, low-spin, octahedral complexes.
Fig. 2
Fig. 2
Common Mn transporters in the cell. A, Transferrin Receptors (TfR) bind to transferrin which has been complexed to Mn+3, Fe+2, or Cu+2. The membrane undergoes endocytosis releasing Mn+3 from transferrin where Mn+3 is reduced to Mn+2 and pumped out of the vesicle by the divalent metal transporter 1 (DMT1). B, DMT1 transporters pump many divalent metals such as Cd+2, Co+2, Fe+2, Mn+2, Ni+2, Pb+2, and Zn+2 across the membrane. C, The voltage gated ZIP8 channels also pump Cd+2, Co+2, Fe+2, Mn+2, and Zn+2 across the membrane. D, Na+ and Mn+2 competitively bind to the choline transporter across the membrane. E, The metal-citrate transporter functions by citrate binding to metals such as Ca+2, Co+2, Fe+3, Mg+2, Mn+2, Na+, Ni+2, and Zn+2 allowing transport across the membrane. Lastly the Ca+2 transporter is a divalent metal transporter (F) which can also transport Ca+2, Cd+2, Mn+2, and Zn+2 across the membrane. These transporters are found in multiple organellar membranes including plasma membrane (PM), nuclear membrane (NM), mitochondrial membrane (MM) and golgi membrane (GM). Note; the representative metals but not all are indicated for transporters.
Fig. 3
Fig. 3
Mn intake and adequate dose range for individuals. Mn absorption is critical to maintain healthy function in all individuals. In Mn-deficient individuals, problems such as impaired growth, skeletal and bone defects, abnormal glucose tolerance, and increased oxidative stress and mitochondrial dysfunction have been observed [59, 183, 184]. The daily recommended intake (DRI) has been found to be 1.8 mg/d for females and 2.3 mg/d for males which is also close to the Low Mn intake level. The upper limit for Mn absorption has been found to be 11 mg/d. Mn toxicity occurs above the upper limit, and toxicity has been calculated to begin at 15 mg/d. Other consequences of excess Mn absorption in addition to apoptosis include manganism, Mn-induced PD, other neurological disorders, increased oxidative stress and mitochondrial dysfunction [–86].
Fig. 4
Fig. 4
Proposed diagram of Mn-induced apoptosis. As Mn accumulates within different organelles in the cell, differing responses can initiate differing caspases in order to activate apoptosis. In the mitochondria, excess Mn causes increased oxidants which leads to cytochrome c (Cyt-c) release and increased transcriptional disruption. This Cyt-c release leads to caspase 8 and 9 activation which activates caspase 3 initiating apoptosis. Mn accumulation decreases membrane potential (Δ Ψ m) and ATP while increasing mitochondrial fission and decreases mitochondrial fusion regulated by Drp-1 and Opa-1, respectively. Mn accumulation in the cytosol can lead to PKCδ activation which also activates caspase 8 followed by activation of caspase 3 to initiate apoptosis. Mn accumulation in the nucleus can lead to chromatin condensation, DNA fragmentation, and increased mRNA levels of caspase 3. Lastly, Mn accumulation in ER leads to increased ER stress, and increases unfolded protein response proteins such as Bip, PERK, Bima and Bax among others. These proteins can initiate caspase 12 activation which also leads to apoptosis through caspase 3. Abbreviations; Drp-1, Dynamin related protein; Opa-1, dynamin like 120 kDa protein, PKCδ , protein kinase c delta; Bip, binding immunoglobulin protein; p-IRE-1, phospho-inositol requiring enzyme 1; PERK, protein kinase RNA-like endoplasmic reticulum kinase; Σ 1R, sigma-1R receptor; CHOP, C/EBP homologous protein; Bim, Bcl-2-like protein 11; Bax, Bcl2-associated X protein.
Fig. 5
Fig. 5
Role of Mn in enzymatic activity. A, SOD2 is found within the mitochondria and catalyzes the dismutation of superoxide into molecular oxygen and Mn+2. Mn+2 (gray) can then be oxidized into Mn+3 (orange) through the catalysis of another molecule of superoxide into hydrogen peroxide. B, In pyruvate carboxylase, Mn+2 interacts with water to stabilize oxaloacetate (OAA) and oxygen from GTP to allow the conversion of OAA to pyruvate (PYR), leading to the conversion of PYR to phosphoenolpyruvate (PEP) [185]. C, Arginase utilizes Mn+2 as a Lewis acid as opposed to its redox properties to accept electrons from water allowing the formation of a hydroxide molecule.
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