Role of hypoxia-inducible factor-prolyl-hydroxylase (HIF-PHD) in mitochondrial pathways of ischemic neuronal death

• Applicant: Professor Dr. Carsten Culmsee
• Subject Area: Molecular and Cellular Neurology and Neuropathology
• Term: from 2018 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 391520971

In neurodegenerative diseases such as Alzheimers and Parkinsons disease, and after cerebral ischemia or traumatic brain injury, the underlying mechanisms of neuronal death determining the irreversible loss of brain tissue and functions share common signaling pathways of programmed cell death. In neurons, these programmed cell death pathways funnel into mitochondria, the key organelles of energy metabolism that are in charge to produce ATP thereby securing neuronal function and survival. Such mitochondrial demise is associated with mitochondrial membrane permeabilization, and the release of pro-apoptotic proteins, such as apoptosis inducing factor (AIF), SMAC/DIABLO or cytochrome c from the intermembrane space into the cytosol and the cell nucleus, where they orchestrate a determined cell death program. It is now well accepted that mitochondrial damage marks the so-called point of no return of programmed cell death, meaning that cells with impaired mitochondria cannot survive. Thus, newly identified mechanistic links between key triggers of neuronal death signaling, such as disrupted Ca2+-homeostasis or oxidative stress, and mitochondrial damage may serve as innovative targets to overcome the current caveat of therapeutic options in the treatment of degenerating neural diseases. Necroptosis and ferroptosis are two emerging forms of regulated necrosis that are regulated by activation of RIP1/RIP3 kinase activation and iron-dependent enzymatic cascades, respectively. Our recent data suggest that in neuronal cells, these paradigms of regulated cell death may be linked to loss of mitochondrial integrity and function with particular impact on the metabolic balance, ROS homeostasis and Ca2+ regulation, and death signaling. In addition, hypoxia-inducible factor (HIF) prolyl-4-hydroxylases (PHDs) emerged as promising target candidates for mitochondrial protection in paradigms of oxidative stress associated with ferroptosis and necroptosis signaling in vitro and in vivo. We hypothesize that HIF-PHDs may serve as potential therapeutic targets in paradigms of regulated necrosis relevant to hypoxic/ischemic brain damage. The outcome of these findings will allow us to dissect the mechanistic involvement of PHDs in cell death signaling in paradigms of necroptosis and ferroptosis, and their potential link to mitochondrial integrity and function in detrimental stress responses in model systems of neuronal cell death induced by oxidative stress and oxygen glucose deprivation in vitro, and after hypoxia-ischemia in vivo. Further, we will address the proposed key role of PHDs in the regulation of neuroinflammatory responses in cultured microglial cells, in brain slices, and after hypoxia ischemia in vivo. Combining the expertise of the applicants in this project allows for providing a unique and unifying picture of the role of PHDs in mechanisms of neurodegeneration and neuroinflammation that may lead to novel strategies of neuroprotection and regeneration.

• DFG Programme: Research Grants
• International Connection: China
• Partner Organisation: National Natural Science Foundation of China
• Cooperation Partner: Professor Changlian Zhu, Ph.D.