Mitochondrial Dynamics & Quality Control

Mitochondrial Dynamics and Mitophagy in Neuronal Ischemia/Reperfusion Injury

Mitochondrial dynamics and mitophagy are constitutive and complex systems that ensure a healthy mitochondrial network through the segregation and subsequent degradation of damaged mitochondria. Disruption of these systems can lead to mitochondrial dysfunction and has been established as a central mechanism of ischemia/reperfusion (I/R) injury. Emerging evidence suggests that mitochondrial dynamics and mitophagy are integrated systems; however, the role of this relationship in the context of I/R injury remains unclear. Our lab is investigating this connection to uncover key pathways involved in cell death following I/R injury.

We utilize novel mouse strains to investigate these mechanisms including dual-reporter mitochondrial quality control (MitoQC) knockin mice (C57BL/6- Gt(ROSA)26Sortm1(CAG- mCherry/GFP)Ganl/J), designer protein-expressing Mitotimer (CAG-CAT-MitoTimer) mice, and mice with conditional knockout (KO) of key mitochondrial proteins (i.e. Drp1, Opa1, Parkin). We also utilize novel quantification methodologies to evaluate mitochondrial dynamics, including the quantitative machine learning mitochondrial morphology classification system (described further here).

Cardiolipin Modification in Neonatal Hypoxia/Ischemia

Current studies are in progress to investigate the role of lipids, specifically cardiolipin, in mitochondrial quality control (QC) following neonatal hypoxia/ischemia injury in neurons. Cardiolipin is a vital mitochondrial lipid, contributing to metabolism, structural integrity and signaling pathways. It is thought that cardiolipin is a key component during mitophagy following injury. Using mass spectrometry, we are evaluating modifications of cardiolipin before and after injury in large animal models. In primary cell culture models, we are utilizing several transgenic mouse lines to manipulate cardiolipin biosynthesis and remodeling in cerebral ischemia/reperfusion injury paradigms.

Relevant Publications:

Anzell AR, Fogo GM, Gurm Z, Raghunayakula S, Wider JM, Maheras KJ, Emaus KJ, Bryson TD, Wang M, Neumar RW, Przyklenk K, Sanderson TH. (2021). Mitochondrial fission and mitophagy are independent mechanisms regarding ischemia/reperfusion injury in primary neurons. Cell Death Dis. 12: 475.

Anzell AR, Maizy R, Przyklenk K, Sanderson TH. (2018). Mitochondrial Quality Control and Disease: Insights into Ischemia-Reperfusion Injury. Mol Neurobiol. 55(3): 2547-2564.

Kumar R, Bukowski MJ, Wider JM, Reynolds CA, Calo L, Lepore B, Tousignant R, Jones M, Przyklenk K, Sanderson TH. (2016). Mitochondrial dynamics following global cerebral ischemia. Mol Cell Neurosci. 76: 68-75.

For a complete listing of publications: click here