Forgotten partners and function regulators of inducible metallothioneins

Abstract

Metallothioneins are peculiar cysteine rich, heat resistant, small cellular plasma proteins expressed through almost all life forms. The currently established biological functions of metallothioneins are the homeostasis of essential metals and protection against toxic transitional metals (TM) alongside defence from oxidative stress by direct scavenging of reactive oxygen and nitrogen species (ROS and RNS). In mammals, among the four main evolutionary conserved forms, only the ubiquitously expressed metallothionein 1 and 2 (here abbreviated as MT) are inducible by TM, oxidative stress, glucocorticoids and starvation among various other stimuli. However, more than sixty years after being discovered, metallothioneins still bear unresolved issues about their possible physiological function and regulation. The biological function of MTs has still not been associated with the in vitro-demonstrated capacity of MT interaction with cellular molecules glutathione (GSH) or adenosine triphosphate (ATP), or with the possibility of direct iron-MT binding in the reducing intracellular environment of some organelles, e.g. lysosomes. Iron as the most abundant cellular TM is also one of the main physiological sources of ROS. Moreover, iron exhibits strain, sex and age differences that reflected ROS generation and MT induction in (patho)physiology and toxicology studies. A recent study showed that iron sex differences follows expression of both ferritin and MT leading to wide implications from essential TM interconnectivity to aging. This review places emphasis on biochemically proven but physiologically ignored interactions of MT with iron to stimulate advanced research for establishing a wide frame of the biological roles of MTs important for health and longevity.

Differential yet integral contributions of Nrf1 and Nrf2 in the human antioxidant cytoprotective response against tert-butylhydroquinone as a pro-oxidative stressor

“…In addition, it is worth mentioning that metallothioneins (MT) cannot only maintain the metal homeostasis in vivo , but also serve as a redox buffer for ROS and other free radicals to play an essential role in the cytoprotection [43]. However, our examinations of MT1E and MT2 unraveled that both genes were not merely insensitive to t BHQ, but were modestly down-regulated by this chemical intervention of WT cells (Fig.…”

Light and heavy ferritin chain expression in the liver and kidneys of Wistar rats: aging, sex differences, and impact of gonadectomy

“…Another interesting finding in our study is intracellular abundance of ferritin-positive vesicles, which may reflect ferritin/ iron lysosomal turnover. Lysosomal iron may be protected with higher expression of inducible metallothioneins (MT) in some proximal tubules, which may attenuate reactive oxygen species (ROS) or directly sequester iron in organelles ( 29 , 30 , 31 , 32 , 33 ). Also, these vesicles can stay in the cell and form lipofuscin as time goes by (aging pigment of incompletely degraded proteins) ( 32 ).…”

“…Interactions between essential and toxic transition metals (TM) and mechanisms that protect or damage the cell/organism have been studied for many years ( 30 ). For iron as an endogenous source of ROS, scavenger interactions with ferritin and MT are of particular interest ( 31 , 32 , 33 , 34 , 35 , 36 , 37 ).…”

Differential Yet Integral Contributions of Nrf1 and Nrf2 in the Human HepG2 Cells on Antioxidant Cytoprotective Response against Tert-Butylhydroquinone as a Pro-Oxidative Stressor

“…In addition, it is worth mentioning that metallothioneins (MT) cannot only maintain the metal homeostasis in vivo, but also serve as a redox buffer for ROS and other free radicals to play an essential role in the cytoprotective process [43]. However, our examinations of MT1E and MT2 unraveled that both genes were not merely insensitive to tBHQ, but were modestly downregulated by this chemical intervention of WT cells (Figure 2J,K, and see Figure S1J,K).…”