Use the Protonmotive Force: Mitochondrial Uncoupling and Reactive Oxygen Species

Abstract

Mitochondrial respiration results in an electrochemical proton gradient, or protonmotive force (pmf), across the mitochondrial inner membrane. The pmf is a form of potential energy consisting of charge (∆ψ) and chemical (∆pH) components, that together drive ATP production. In a process called uncoupling, proton leak into the mitochondrial matrix independent of ATP production dissipates the pmf and energy is lost as heat. Other events can directly dissipate the pmf independent of ATP production as well, such as chemical exposure or mechanisms involving regulated mitochondrial membrane electrolyte transport. Uncoupling has defined roles in metabolic plasticity and can be linked through signal transduction to physiologic events. In the latter case, the pmf impacts mitochondrial reactive oxygen species (ROS) production. Although capable of molecular damage, ROS also have signaling properties that depend on the timing, location, and quantity of their production. In this review, we provide a general overview of mitochondrial ROS production, mechanisms of uncoupling, and how these work in tandem to affect physiology and pathologies, including obesity, cardiovascular disease, and immunity. Overall, we highlight that isolated bioenergetic models-mitochondria and cells-only partially recapitulate the complex link between the pmf and ROS signaling that occurs in vivo.

Traumatic stress history interacts with chronic peripheral inflammation to alter mitochondrial function of synaptosomes in a sex-specific manner

“…We did not observe changes in physical characteristics of mitochondrial structure or synaptic enrichment in male samples which suggests that effects on respiration were the product of an overall decrease in mitochondrial function via a mechanism not directly related to mitochondrial health. Potential explanations for this phenomenon could lie in increased rate of mitophagy or a decrease in the mitochondrial proton motive force in a mechanism not directly assessed through our analysis (Berry et al, 2018). Moreover, the null results in central ROMO1 expression data suggest that mitochondrial respiration differences are not due to altered levels of reactive oxygen species in the brain, but the elevated ROMO1 concentrations in the blood may implicate peripheral effects of reactive oxygen which were not detectable at the expression level in the brain.…”

Manipulation of Transmembrane Transport by Synthetic K+ Ionophore Depsipeptides and Its Implications in Glucose‐Stimulated Insulin Secretion in β‐Cells

“…The transport rates are controlled by the membrane potential (i.e., electrogenic valinomycin, JG100 , JG121 , and JG115 ) or pH gradient (i.e., electroneutral JG115B − ⋅ K + ) . Thus, upon removing the rate‐limiting step, which is H + transport, by adding FCCP (carbonyl cyanide‐ p ‐(trifluoromethoxy)hydrazine), a specific proton transporter (Figure b), the K + transport activities increased remarkably by two ( JG115 , JG115B , JG121 ) to three ( JG100 ) orders o of magnitude for the electrogenic JG100⋅ K + , JG121⋅ K + , and JG115⋅ K + carriers (Table ). Despite a minimal structural modification, a lower activity was observed for the electroneutral carrier JG115B − ⋅ K + , which is seven times less active and probably less membrane‐permeable than electrogenic JG100⋅ K + in the presence of FCCP.…”

“…The transport rates are controlled by the membrane potential (i.e.,electrogenicvalinomycin, JG100, JG121,a nd JG115)o rpH gradient (i.e., electroneutral JG115B À ·K + ). [25,26] Thus,u pon removing the rate-limiting step, which is H + transport, by adding FCCP( carbonyl cyanide-p-(trifluoromethoxy)hydrazine), as pecific proton transporter [27,28] (Figure 1b), the K + transport activities increased remarkably by two (JG115, JG115B, JG121)t ot hree (JG100) orders oo fm agnitude for the electrogenic JG100·K + , JG121·K + ,a nd JG115·K + carriers ( Table 1). Despite am inimal structuralm odification,alower activity was observedf or the electroneutral carrier JG115B À ·K + ,w hich is seven times less active and probablyl ess membrane-permeable than electrogenic JG100·K + in the presence of FCCP.M oreover,t he pseudo-first-order initial transport rate constants, k K + = 0.0048 and k Na + = 0.0006 s À1 ,f or JG115B indicate as electivity (S)f or K + of S K + /Na + = 8i nt he absence of FCCP,w hichi ncreases strongly to S K + /Na + = 129 (k K + = 0.3352 and k Na + = 0.0026 s À1 )i n the presence of FCCP.…”

Novel imaging biomarkers for mapping the impact of mild mitochondrial uncoupling in the outer retina in vivo

“…Ex vivo studies suggest that mitochondrial protonophores stimulate metabolism but only if sufficient reserve capacity is available [3][4][5]. For example, if mitochondrial reserve capacity is relatively limited, then DNP is not expected to increase respiration by much with correspondingly little change in the production of oxygen free radicals, and CO 2 and waste water [3,6,7]. On the other hand, neurons with a relatively larger mitochondrial respiratory reserve capacity exposed to DNP will show relatively larger reductions in their local levels of oxygen with greater flux through the electron transport chain.…”

“…On the other hand, neurons with a relatively larger mitochondrial respiratory reserve capacity exposed to DNP will show relatively larger reductions in their local levels of oxygen with greater flux through the electron transport chain. In turn, this results in a larger reduction in the leakage of damaging oxygen free radicals from the mitochondria; CO 2 and water production are also expected to increase with higher metabolic rate leading to greater water removal in, for example, the outer retina [5,6,8]. Importantly, as recently reviewed, preclinical studies indicate that low doses of DNP can be useful as safe neuroprotective agents in a range of diseases [9].…”