Changes in specific lipids regulate BAX‐induced mitochondrial permeability transition

Abstract

Recent evidence suggests the existence of lipid microdomains in mitochondria, apparently coexisting as structural elements with some of the mitochondrial permeability transition pore‐forming proteins and members of the Bcl‐2 family. The aim of this study was to investigate the relevance of the main components of membrane microdomains (e.g. cholesterol and sphingolipids) in activation of the mitochondrial permeability transition pore (mPTP) by recombinant BAX (rBAX). For this purpose, we used chemically modified renal cortex mitochondria and renal cortex mitochondria from hypothyroid rats that show a modified mitochondrial lipid composition in vivo. Oligomeric rBAX induced an enhanced permeability conformation in the mPTP of control mitochondria. rBAX failed to induce mPTP opening when the cholesterol and ganglioside content of mitochondria were modified with the chelator methyl‐beta‐cyclodextrin. Accordingly, hypothyroid mitochondria, with endogenously lower cholesterol and ganglioside content, showed resistance to mPTP opening induced by rBAX. These observations suggest that enriched cholesterol and ganglioside domains in the mitochondrial membranes may determine BAX interaction with the mPTP. An intriguing observation was that chemical extraction of cholesterol and ganglioside in control mitochondria did not have an effect on rBAX insertion. Conversely, in hypothyroid mitochondria, rBAX insertion was diminished dramatically compared with control mitochondria. The membrane and protein changes associated with thyroid status and their possible role in rBAX docking into the membranes are discussed.

The Bladder Tumor Suppressor Protein TERE1 (UBIAD1)Modulates Cell Cholesterol: Implications for Tumor Progression

“…However, there is also a separate recognition that elevated intracellular cholesterol in non-hormone-dependent tumor cells can contribute to progression based on numerous reports of interference with multiple pathways of growth signaling and apoptosis (Zhuang et al, 2005;Li et al, 2006;Swinnen et al, 2006;Adam et al, 2007;Freeman et al, 2007;Martinez-Abundis et al, 2007;Oh et al, 2007;Christenson et al, 2008;Patra, 2008). The link between intracellular cholesterol and tumor progression has been found in hepatocellular carcinoma, colon, breast, head and neck, and melanoma cancers, either with tumor specimens and/or studies in cancer cell lines (Schabath et al, 2006;Baruthio et al, 2008;Montero et al, 2008).…”

Synaptic and Non-Synaptic Mitochondria in Hippocampus of Adult Rats Differ in Their Sensitivity to Hypothyroidism

“…Yehuda-Shnaidman et al (2005) have proposed that TH-induced mitochondrial uncoupling could be ascribed to low conductance mPT gating mediated by TH-induced increase in mitochondrial pro-apoptotic combined with a decrease in mitochondrial anti-apoptotic proteins of the Bax-Bcl2 family. Conversely, in hypothyroid mitochondria, Bax insertion was dramatically diminished compared with control mitochondria (Martınez-Abundis et al 2007). In this context, we have determined the content of two pro-apoptotic proteins in hypothyroid mitochondria-BH3-only proteinBad and K-Ras.…”

Cholesterol Effects on BAX Pore Activation

“…However, the mitochondrial membrane environment is complex and steroid oxidation an active process in these organelles [23,24]. Therefore, when multiple membrane parameters are changed decreased permeability transition pore activation has also been reported [34]. Our studies have focused on cholesterol in a controlled experimental situation to understand the mechanism by which cholesterol inhibits BAX pore activation.…”

“…Recently bilayer cholesterol content has been shown to influence BAX oligomerization and trypsin resistance in liposomes and mitochondria [33]. Others have reported complex relationships among lipids, cholesterol, BAX and permeability transition pore activation [34]. These observations have been used to explain the effects of cholesterol upon cellular apoptosis.…”