Mitochondrial proteases in cell death and neuroprotection

LACTB

LACTB is a conserved mammalian serine protease deriving from a bacterial penicillin-binding protein. LACTB is localized in the mitochondrial intermembrane compartment and can form a large polymer with a molecular weight of several million daltons. LACTB interacts with proteins involved in core energy metabolism. LACTB may play a role in mediating the neuroprotective effect of beta-lactam antibiotics. Our goals are to identify catalytic substrates of LACTB, to clarify the molecular mechanism for LACTB’s polymerization, and to elucidate the physiological function of LACTB-polymers.

 

Calpains

Calpains are calcium-activated neutral cysteine proteases constituting a family of distinct isozymes that differ in structure and tissue distribution. Disturbances in the regulation of calpains occur in several disorders including ischemia-reperfusion injury, Alzheimer’s disease, muscular dystrophy, and cancer. We have recently demonstrated that some calpains are localized in mitochondria. Our current studies are aimed at detecting interactions between calpains and mitochondrial apoptosis mediators.

 

The mitochondrial permeability transition

The mitochondrial permeability transition pore, or PTP, is a megachannel located in the inner mitochondrial membrane. Opening of the PTP channel leads to a cellular bioenergetic crisis and release of mitochondrial apoptotic proteins, e.g. cytochrome c, to the cytosol. During normal cell life the PTP remains closed. However, if high quantities of calcium are accumulated in the cell, e.g. induced by excitotoxic stimulation, the PTP may open leading to cell death. The molecular machinery of the PTP is incompletely understood. Our goal is to elucidate the molecular mechanism of the PTP channel and we are particularly interested in the role mitochondrial proteases.

 

Page updated June 28, 2011
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