Mitochondrial function in hypoxic ischemic injury and influence of aging

Abstract

Mitochondria are a major target in hypoxic/ischemic injury. Mitochondrial impairment increases with age leading to dysregulation of molecular pathways linked to mitochondria. The perturbation of mitochondrial homeostasis and cellular energetics worsens outcome following hypoxic-ischemic insults in elderly individuals. In response to acute injury conditions, cellular machinery relies on rapid adaptations by modulating posttranslational modifications. Therefore, post-translational regulation of molecular mediators such as hypoxia-inducible factor 1α (HIF-1α), peroxisome proliferator-activated receptor γ coactivator α (PGC-1α), c-MYC, SIRT1 and AMPK play a critical role in the control of the glycolytic-mitochondrial energy axis in response to hypoxic-ischemic conditions. The deficiency of oxygen and nutrients leads to decreased energetic reliance on mitochondria, promoting glycolysis. The combination of pseudohypoxia, declining autophagy, and dysregulation of stress responses with aging adds to impaired host response to hypoxic-ischemic injury. Furthermore, intermitochondrial signal propagation and tissue wide oscillations in mitochondrial metabolism in response to oxidative stress are emerging as vital to cellular energetics. Recently reported intercellular transport of mitochondria through tunneling nanotubes also play a role in the response to and treatments for ischemic injury. In this review we attempt to provide an overview of some of the molecular mechanisms and potential therapies involved in the alteration of cellular energetics with aging and injury with a neurobiological perspective.

Keywords: Alzheimer’s disease; Apoptosis; Autophagy; Blood brain barrier; Hypoxia; Intermitochondrial signal propagation; Ischemia/reperfusion; Mitokine; Mitoquinone; Nuclear-mitochondria cross-talk; Oxidative phosphorylation; Parkinson’s disease; Pseudohypoxia; Resveratrol, SIRT1, sirtuins; Stroke, myocardial infarction; Tempol; Tunneling nanotube.

Figure 1. Critical molecular mediators in hypoxia/ischemia

HIF-α is a critical modulator of hypoxic response. SIRT1 deacetylates Lys674 of HIF-1α, which inhibits P300 binding and decreases HIF-1α signaling. During hypoxia, SIRT1 is suppressed consequent to decreased NAD⁺, and facilitates HIF-1 signaling (Lim et al., 2010). HIF-1α induces gene transcription leading to activation of many mediators including glycolytic enzymes, and also activates pyruvate dehydrogenase kinase 1 (PDK1) which inhibits pyruvate dehydrogenase (PDH) leading to inhibition of mitochondrial oxidation. PGC-1α activation leads to NRF, ERR, and PPAR activation, which increase mitochondrial function and biogenesis.

Figure 2. SIRT1-AMPK axis in resveratrol mediated metabolic regulation

Resveratrol has been demonstrated to be an allosteric activator of SIRT1. (Price et al, 2013). Resveratrol may also act through phosphodiesterase (PDE) leading to AMPK activation, increased NAD+ and phosphorylation of Pgc-1α (Park et al, 2012). SIRT1 deacetylates Pgc-1α. Phosphorylated and deacetylated Pgc-1α augments mitochondrial biogenesis and function. The pathway of action of resveratrol has been suggested to be dose-dependent (Price et al, 2013). Among other functions of SIRT1 include deacetylation and inactivation of Nfkb and p53. P= phosphate group, Ac= acetyl group.