Decline in cytochrome c oxidase activity in rat-brain mitochondria with aging. Role of peroxidized cardiolipin and beneficial effect of melatonin

Petrosillo, Giuseppe; Benedictis, Valentina De; Ruggiero, Francesca; Paradies, Giuseppe

doi:10.1007/s10863-013-9505-0

Cited by 60 publications

(31 citation statements)

References 62 publications

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“…The loss of cardiolipin can explain the decreased mitochondrial membrane fluidity reported in aged rats (Lee et al ., ). It is also consistent with the findings that age‐related decline in complex IV activity can be restored by exogenously added cardiolipin or cyt c (Paradies et al ., ; O'Toole et al ., ; Petrosillo et al ., ).…”

Section: Aging Leads To Alterations In Lipid Composition Of the Immmentioning

confidence: 97%

First‐in‐class cardiolipin‐protective compound as a therapeutic agent to restore mitochondrial bioenergetics

Szeto

2014

British J Pharmacology

438

390

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A decline in energy is common in aging, and the restoration of mitochondrial bioenergetics may offer a common approach for the treatment of numerous age‐associated diseases. Cardiolipin is a unique phospholipid that is exclusively expressed on the inner mitochondrial membrane where it plays an important structural role in cristae formation and the organization of the respiratory complexes into supercomplexes for optimal oxidative phosphorylation. The interaction between cardiolipin and cytochrome c determines whether cytochrome c acts as an electron carrier or peroxidase. Cardiolipin peroxidation and depletion have been reported in a variety of pathological conditions associated with energy deficiency, and cardiolipin has been identified as a target for drug development. This review focuses on the discovery and development of the first cardiolipin‐protective compound as a therapeutic agent. SS‐31 is a member of the Szeto‐Schiller (SS) peptides known to selectively target the inner mitochondrial membrane. SS‐31 binds selectively to cardiolipin via electrostatic and hydrophobic interactions. By interacting with cardiolipin, SS‐31 prevents cardiolipin from converting cytochrome c into a peroxidase while protecting its electron carrying function. As a result, SS‐31 protects the structure of mitochondrial cristae and promotes oxidative phosphorylation. SS‐31 represents a new class of compounds that can recharge the cellular powerhouse and restore bioenergetics. Extensive animal studies have shown that targeting such a fundamental mechanism can benefit highly complex diseases that share a common pathogenesis of bioenergetics failure. This review summarizes the mechanisms of action and therapeutic potential of SS‐31 and provides an update of its clinical development programme. Linked Articles This article is part of a themed issue on Mitochondrial Pharmacology: Energy, Injury & Beyond. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2014.171.issue-8

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Section: Aging Leads To Alterations In Lipid Composition Of the Immmentioning

confidence: 97%

First‐in‐class cardiolipin‐protective compound as a therapeutic agent to restore mitochondrial bioenergetics

Szeto

2014

British J Pharmacology

438

390

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“…By doing so, melatonin is believed to protect against ischemia-reperfusion induced damage to the heart [138]; it also attenuates mitochondrial dysfunction in sepsis [139,140], multiple sclerosis [141], doxorubicin-induced cellular senescence [142], in senescence-accelerated mice [143][144][145], and during aging [134,[146][147][148]. It was also found that the protection of cardiolipin from peroxidation in mitochondria was an important means by which melatonin prevents mitochondrial dysfunction [138,146,[149][150][151].…”

Section: Protection and Improvement Of Mitochondrial Function By Melamentioning

confidence: 99%

Melatonin: a well‐documented antioxidant with conditional pro‐oxidant actions

Zhang

2014

Journal of Pineal Research

705

565

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Melatonin (N-acetyl-5-methoxytryptamine), an indoleamine produced in many organs including the pineal gland, was initially characterized as a hormone primarily involved in circadian regulation of physiological and neuroendocrine function. Subsequent studies found that melatonin and its metabolic derivatives possess strong free radical scavenging properties. These metabolites are potent antioxidants against both ROS (reactive oxygen species) and RNS (reactive nitrogen species). The mechanisms by which melatonin and its metabolites protect against free radicals and oxidative stress include direct scavenging of radicals and radical products, induction of the expression of antioxidant enzymes, reduction of the activation of pro-oxidant enzymes, and maintenance of mitochondrial homeostasis. In both in vitro and in vivo studies, melatonin has been shown to reduce oxidative damage to lipids, proteins and DNA under a very wide set of conditions where toxic derivatives of oxygen are known to be produced. Although the vast majority of studies proved the antioxidant capacity of melatonin and its derivatives, a few studies using cultured cells found that melatonin promoted the generation of ROS at pharmacological concentrations (lM to mM range) in several tumor and nontumor cells; thus, melatonin functioned as a conditional pro-oxidant. Mechanistically, melatonin may stimulate ROS production through its interaction with calmodulin. Also, melatonin may interact with mitochondrial complex III or mitochondrial transition pore to promote ROS production. Whether melatonin functions as a pro-oxidant under in vivo conditions is not well documented; thus, whether the reported in vitro pro-oxidant actions come into play in live organisms remains to be established.

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“…Melatonin as a mitochondrial antioxidant protects cardilipin from pro-oxidation and therefore maintains the closed configuration of AAC. The protective effects of melatonin on cardilipin and MPTP are well documented [164,165,166,167]. …”

Section: Melatonin: a Potent Protector Of Mitochondriamentioning

confidence: 99%

Melatonin: A Mitochondrial Targeting Molecule Involving Mitochondrial Protection and Dynamics

Tan

Manchester

Qin

et al. 2016

IJMS

322

256

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Melatonin has been speculated to be mainly synthesized by mitochondria. This speculation is supported by the recent discovery that aralkylamine N-acetyltransferase/serotonin N-acetyltransferase (AANAT/SNAT) is localized in mitochondria of oocytes and the isolated mitochondria generate melatonin. We have also speculated that melatonin is a mitochondria-targeted antioxidant. It accumulates in mitochondria with high concentration against a concentration gradient. This is probably achieved by an active transportation via mitochondrial melatonin transporter(s). Melatonin protects mitochondria by scavenging reactive oxygen species (ROS), inhibiting the mitochondrial permeability transition pore (MPTP), and activating uncoupling proteins (UCPs). Thus, melatonin maintains the optimal mitochondrial membrane potential and preserves mitochondrial functions. In addition, mitochondrial biogenesis and dynamics is also regulated by melatonin. In most cases, melatonin reduces mitochondrial fission and elevates their fusion. Mitochondrial dynamics exhibit an oscillatory pattern which matches the melatonin circadian secretory rhythm in pinealeocytes and probably in other cells. Recently, melatonin has been found to promote mitophagy and improve homeostasis of mitochondria.

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Decline in cytochrome c oxidase activity in rat-brain mitochondria with aging. Role of peroxidized cardiolipin and beneficial effect of melatonin

Cited by 60 publications

References 62 publications

First‐in‐class cardiolipin‐protective compound as a therapeutic agent to restore mitochondrial bioenergetics

First‐in‐class cardiolipin‐protective compound as a therapeutic agent to restore mitochondrial bioenergetics

Melatonin: a well‐documented antioxidant with conditional pro‐oxidant actions

Melatonin: A Mitochondrial Targeting Molecule Involving Mitochondrial Protection and Dynamics

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