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Review
. 2015 Apr;47(1-2):173-88.
doi: 10.1007/s10863-014-9583-7. Epub 2014 Oct 8.

Sex differences in mitochondrial (dys)function: Implications for neuroprotection

Tyler G Demarest  1 , Margaret M McCarthy
Affiliations
Review

Sex differences in mitochondrial (dys)function: Implications for neuroprotection

Tyler G Demarest et al. J Bioenerg Biomembr. 2015 Apr.

Abstract

Decades of research have revealed numerous differences in brain structure size, connectivity and metabolism between males and females. Sex differences in neurobehavioral and cognitive function after various forms of central nervous system (CNS) injury are observed in clinical practice and animal research studies. Sources of sex differences include early life exposure to gonadal hormones, chromosome compliment and adult hormonal modulation. It is becoming increasingly apparent that mitochondrial metabolism and cell death signaling are also sexually dimorphic. Mitochondrial metabolic dysfunction is a common feature of CNS injury. Evidence suggests males predominantly utilize proteins while females predominantly use lipids as a fuel source within mitochondria and that these differences may significantly affect cellular survival following injury. These fundamental biochemical differences have a profound impact on energy production and many cellular processes in health and disease. This review will focus on the accumulated evidence revealing sex differences in mitochondrial function and cellular signaling pathways in the context of CNS injury mechanisms and the potential implications for neuroprotective therapy development.

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Figures

Fig. 1
Fig. 1
Sources of Sex Differences in the Brain. The bipotential gonad is directed towards testis development by the SRY gene on the Y chromosome. Testosterone production begins during fetal life and surges again at birth and then remains low until puberty. Steroids impact numerous endpoints in the developing brain, many of which will endure into adulthood. In females the ovary develops due to the lack of SRY and remains quiescent until puberty at which time estradiol production is cyclical. Genes on the X and Y chromosome are capable of influencing brain in behavior throughout life in manners still not well understood
Fig. 2
Fig. 2
Sex Dependent Cell Death Proclivity and Interactions. Male predominant pathways are in blue, females in pink, and interacting pathways in black. Abbreviations: mitochondrial permeability transition pore (mPTP); neuronal/mitochondrial nitric oxide synthase (nNOS/mtNOS); tricarboxylic acid cycle (TCA cycle); nicotinamide adenine dinucleotide (NAD+); Reactive oxygen species (ROS); reactive nitrogen species (RNS); adenosine triphosphate (ATP);cytochrome c (CytC); poly(ADP-ribose) polymerase 1 (PARP-1); poly(ADP-ribose) (PAR); poly(ADP-ribose) glycohydrolase (PARG); ADP-ribose (ADPr); apoptosis inducing factor (AIF); X-linking inhibition of apoptosis (XIAP); Second mitochondria-derived activator of caspases (SMAC). Inhibitor of caspase activated DNase (ICAD); Caspase activated DNase (CAD); Endonuclease G (EndoG)
Fig. 3
Fig. 3
Summary of Sexually Dimorphic Cell signaling following CNS Injury. Male predominant pathways are represented in blue and female predominant pathways in pink. Following CNS injury, extracellular glutamate activates extrasynaptic NMDARs triggering Ca2+ influx. Intracellular Ca2+ activates NOS, to a higher degree in male cells. Mitochondrial Ca2+ uptake increases oxidative phosphorylation, ROS generation, subsequent DNA damage and mitochondrial swelling. ROS mediated damage is greater in male cells likely due to poorer antioxidant defense systems vs. females, (i.e. glutathioned peroxidase; GPx), which activates PARP-1 consumption of NAD+to generate PAR and ADPr. In surviving cells, ROS oxidation of cardiolipin, likely more common in males, causes a conformational flip to the outer membrane where oxidized cardiolipin binds LC3 to promote mitophagy, removing damaged organelles. In male cells, the combination of peroxide and ADPr activates TRPM2 cation channels further exacerbating Ca2+ influx and oxidative damage. In severe injury, Ca2+ overload can lead to activation of the mitochondrial permeability transition pore (mPTP), acute loss of ATP and necrosis or mitochondrial release of cytochrome c and AIF. Cytochrome c release results in caspase-dependent apoptosis in female cells while the combination of NAD depletion and AIF release leads to caspase-independent parthanatos in male cells
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