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 false(O2−⋅false) or hydrogen peroxide (H2O2) 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 health risk assessment. Furthermore, application of improved mass spectrometry-based proteomic methods will lead to further understanding of the critical targets contributing to disease risk.

Neuroaxonal Dystrophy in Calcium-Independent Phospholipase A2β Deficiency Results from Insufficient Remodeling and Degeneration of Mitochondrial and Presynaptic Membranes

“…4-HNE is considered to be an oxidized secondary product of lipids including CL (Liu et al, 2011) and would reflect mitochondrial dysfunction (Roede and Jones, 2010). Because CL was increased approximately threefold in iPLA 2 ␤-KO mice and the distribution of 4-HNE was not correlated with increased PCs with Figure 8.…”

“…The fact that the distribution of 4-HNE was inconsistent with that of PAS-positive granules, which were identical to abnormal mitochondria containing dense granules, and the distal parts of axons were positive for 4-HNE suggested that 4-HNE might be accumulated in the distal part of degenerated axons that lacked axonal flow for transport of PAS-positive granules and that 4-HNE might not be massively produced until the mitochondrial double membranes had been disrupted. The presence of 4-HNE in axons might also aggravate axonal degeneration by attacking targets within the cell and expanding into the extracellular space (Roede and Jones, 2010).…”

Emerging Associations of the ALDH2*2 Polymorphism with Disease Susceptibility

“…ALDH2*2 and disease unrelated to alcohol consumption: Ischemia occurs when blood flow to a certain tissue system is decreased, which can ultimately damage the tissue. In myocardial ischemia, most of the cardiac damage that occurs is believed to be due to excessive generation of reactive oxygen species, leading to peroxidation of unsaturated fatty acids that can form toxic end products such as the reactive aldehyde, 4-hydroxynonenal (4-HNE) [70,71]. Due to damage to the cardiac myocytes, excessive production of 4-HNE may ultimately impair cardiac contractility.…”

Contemporary Radiation Countermeasure

“…Further, gamma-tocotrienol (GT3) also acts as a radioprotector for hematopoietic stem cells and progenitor cells in sub-lethally irradiated mice 37 . Mitochondria-targeted antioxidants would be important molecules providing protection from reactive oxygen species as mitochondria dysfunction by excess radicals can lead to cell death 39,40 . One such approach directed at the mitochondria in protecting cells from ionising radiation damage with Tempol 41 (Fig.…”