Upregulation of the mitochondrial Lon Protease allows adaptation to acute oxidative stress but dysregulation is associated with chronic stress, disease, and aging

Abstract

The elimination of oxidatively modified proteins is a crucial process in maintaining cellular homeostasis, especially during stress. Mitochondria are protein-dense, high traffic compartments, whose polypeptides are constantly exposed to superoxide, hydrogen peroxide, and other reactive species, generated by ‘electron leakage’ from the respiratory chain. The level of oxidative stress to mitochondrial proteins is not constant, but instead varies greatly with numerous metabolic and environmental factors. Oxidized mitochondrial proteins must be removed rapidly (by proteolytic degradation) or they will aggregate, cross-link, and cause toxicity. The Lon Protease is a key enzyme in the degradation of oxidized proteins within the mitochondrial matrix. Under conditions of acute stress Lon is highly inducible, possibly with the oxidant acting as the signal inducer, thereby providing increased protection. It seems that under chronic stress conditions, however, Lon levels actually decline. Lon levels also decline with age and with senescence, and senescent cells even lose the ability to induce Lon during acute stress. We propose that the regulation of Lon is biphasic, in that it is up-regulated during transient stress and down-regulated during chronic stress and aging, and we suggest that the loss of Lon responsiveness may be a significant factor in aging, and in age-related diseases.

Hydrogen peroxide mediated mitochondrial UNG1-PRDX3 interaction and UNG1 degradation

“…Further study revealed that the ROSinduced degradation of UNG1 was not proteasome dependent; rather, LonP1 was responsible for UNG1 degradation under oxidative stress. LonP1 is a mitochondrial ATP-dependent protease [50], which is induced by oxidative stress to degrade oxidized proteins within the mitochondrial matrix [50][51][52][53][54]. Although the molecular mechanisms leading to degradation of UNG1 are still not clear, our study reveals that ROS promotesLonP1-dependent UNG1 degradation whereas the UNG1-PRDX3 interaction protects UNG1 from ROS-mediated degradation.…”

Effects of intermittent hypoxia on oxidative stress and protein degradation in molluscan mitochondria

“…ATP-dependent mitochondrial proteases (including Lon and ClpXP proteases) are essential components of the mitochondrial protective system against oxidative stress. They degrade damaged mitochondrial proteins, preventing their accumulation and aggregation, and often demonstrate selectivity for oxidatively damaged proteins (Ngo et al, 2013). High steady-state activity of ATP-dependent mitoproteases in clam mitochondria may therefore protect these organelles during oxygen fluctuations by maintaining integrity of the mitochondrial proteome.…”

“…Suppression of the activity of ATP-dependent mitoproteases leads to decreased mitochondrial respiration, elevated ROS production and upregulated expression of mitochondrial chaperones reflecting proteotoxicity in diverse organisms including mammals, plants and fungi (Pinti et al, 2015;Quirós et al, 2014Quirós et al, , 2015. Studies in rodents showed that ATP-dependent mitoproteases play a key role in mitigating oxidative damage and cellular injury during H/R stress (Bezawork-Geleta et al, 2015;Ngo et al, 2013;Teng et al, 2013). However, the involvement of mitoproteases in the response to intermittent hypoxia has not been extensively studied in hypoxiatolerant organisms including marine mollusks.…”

The emerging theme of redox bioenergetics in health and disease

“…Under conditions of acute stress, Lon is rapidly induced; but under conditions of chronic stress, aging, and senescence, the levels decline leaving the cell particularly vulnerable to bioenergetic dysfunction. [80] The oxygen binding site in the mitochondrion at cytochrome c oxidase is well known to be the site of interaction with NO. [53] Since the synthesis of NO by nitric oxide synthases also requires oxygen, this establishes an interesting and potentially important biological interaction between oxygen and NO gradients in organs and tissues.…”