Mitochondrial Apoptosis

Mitochondrial (or “intrinsic”) apoptosis plays a critical role in organismal development, and its dysregulation is implicated in diseases ranging from neurodegeneration to cancer. As the name suggests, this cell death pathway originates in the mitochondria. Recent studies have identified the key roles played by mitochondrial lipid species, and lipid-derived signaling molecules. Dysfunction in mitochondria commonly leads to increases in reactive oxygen species (ROS), which in turn facilitate damage to proteins, DNA and lipids, via peroxidation reactions. The mitochondrial protein cytochrome c has been shown to catalyze the peroxidation of particular lipid species in mitochondria (cardiolipins), and thus generate important pro-apoptotic signals.

The Van der Wel lab is engaged in NIH-funded research into the molecular processes involved in the generation of the chemically modified mitochondrial lipids, as well as the consequences of the generated signaling molecules. We are using solid-state NMR spectroscopy to study the interactions between mitochondrial protein cytochrome c and membranes containing the mitochondrial lipid cardiolipin [1]. Our experiments leverage the unique information that solid-state NMR can provide on the interactions between proteins and lipids [2]. At the same time, the ssNMR studies are combined with functional assays as well as various other biophysical measurements, to provide a multifaceted perspective on these lethal mitochondrial events.

 

Related publications:

  1. Mandal et al. (2015) Structural changes and pro-apoptotic peroxidase activity of cardiolipin-bound mitochondrial cytochrome c. Biophys. J. 109(9): 1873–1884 (DOI)
  2. Van der Wel (2014) Lipid Dynamics and Protein-Lipid Interactions in Integral Membrane Proteins: Insights from Solid-State NMR.eMagRes.  3: 111–118 (DOI) (PDF download)