Reactive species and mitochondrial dysfunction: mechanistic significance of 4-hydroxynonenal

Abstract

Mitochondrial dysfunction is a global term used in the context of "unhealthy" mitochondria. In practical terms, mitochondria are extremely complex and highly adaptive in structure, chemical and enzymatic composition, subcellular distribution and functional interaction with other components of cells. Consequently, altered mitochondrial properties that are used in experimental studies as measures of mitochondrial dysfunction often provide little or no distinction between adaptive and maladaptive changes. This is especially a problem in terms of generation of oxidant species by mitochondria, wherein increased generation of superoxide anion radical (O(2*)(-)) or hydrogen peroxide (H(2)O(2)) is often considered synonymously with mitochondrial dysfunction. However, these oxidative species are signaling molecules in normal physiology so that a change in production or abundance is not a good criterion for mitochondrial dysfunction. In this review, we consider generation of reactive electrophiles and consequent modification of mitochondrial proteins as a means to define mitochondrial dysfunction. Accumulated evidence indicates that 4-hydroxynonenal (HNE) modification of proteins reflects mitochondrial dysfunction and provides an operational criterion for experimental definition of mitochondrial dysfunction. Improved means to detect and quantify mitochondrial HNE-protein adduct formation could allow its use for environmental healthrisk assessment. Furthermore, application of improved mass spectrometry-based proteomic methods will lead to further understanding of the critical targets contributing to disease risk.

Fig. 1

4-HNE is derived from lipid hydroperoxides generated during the process of lipid peroxidation. Lipid peroxidation is initiated by a free-radical-mediated abstraction of a hydrogen from a bisallylic carbon of a PUFA. This forms a carbon centered radical, which rearranges to form a conjugated diene. Reaction of this radical with molecular oxygen results in a peroxyl radical, which, in the presence of an additional PUFA acyl chain, can abstract an additional hydrogen forming a lipid hydroperoxide.

Fig. 2

4-HNE contains a reactive center located on carbon 3 (A). This reactive center can then form a Michael addition product with a protein thiol (B).

Fig. 3

Sequence alignment of TIM44 (A) and TOM40 (B) illustrate conserved cysteine residues across multiple species. The cysteine residues highlighted by bold type and boxed were found by Wong and Liebler [2008] to be modified by the model electrophile BMCC.

Fig. 4

A general schematic representation demonstrating how 4-HNE can cause mitochondrial dysfunction is shown. ROS produced within the mitochondrion can result in lipid peroxidation and 4-HNE. This aldehyde can diffuse into the matrix and/or the IMS resulting in protein modification. It is this protein modification that causes altered protein activity resulting in mitochondrial dysfunction. [Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com.]