Activation of mitochondrial fusion provides a new treatment for mitochondria-related diseases

Abstract

Mitochondria fragmentation destabilizes mitochondrial membranes, promotes oxidative stress and facilitates cell death, thereby contributing to the development and the progression of several mitochondria-related diseases. Accordingly, compounds that reverse mitochondrial fragmentation could have therapeutic potential in treating such diseases. BGP-15, a hydroxylamine derivative, prevents insulin resistance in humans and protects against several oxidative stress-related diseases in animal models. Here we show that BGP-15 promotes mitochondrial fusion by activating optic atrophy 1 (OPA1), a GTPase dynamin protein that assist fusion of the inner mitochondrial membranes. Suppression of Mfn1, Mfn2 or OPA1 prevents BGP-15-induced mitochondrial fusion. BGP-15 activates Akt, S6K, mTOR, ERK1/2 and AS160, and reduces JNK phosphorylation which can contribute to its protective effects. Furthermore, BGP-15 protects lung structure, activates mitochondrial fusion, and stabilizes cristae membranes in vivo determined by electron microscopy in a model of pulmonary arterial hypertension. These data provide the first evidence that a drug promoting mitochondrial fusion in in vitro and in vivo systems can reduce or prevent the progression of mitochondria-related disorders.

BGP-15 Protects Mitochondria in Acute, Acetaminophen Overdose Induced Liver Injury

“…Observations published recently suggest that BGP-15 affects mitochondrial fusion-fission cycle, preventing mitochondrial fragmentation [23]. In accordance with these observations, BGP-15 administration results in a decrease in the number of damaged mitochondria as it has been demonstrated in our recent study, which is accompanied with the increase in mitophagy.…”

“…Its various experimental effects have been demonstrated in a series of different animal models and also in cell cultures. These are protective effects influencing among others heart, skeletal muscle, liver, oocytes, skin and show the involvement of mitochondria [5,[18][19][20][21][22][23][24]. Hindrance of ROS elevation and also moderation in JNK activation by BGP-15 have been shown in different experimental models [18].…”

“…We have published protective effects by BGP-15 in acute APAP induced liver injury; it largely counteracted MOMP [5]. In addition, mitochondrial dysfunction and even ER stress were also affected by BGP-15 in different experimental systems [19,22,23]. Therefore, the effect of BGP-15 was further investigated focusing mainly on morphological signs of the involvement of mitochondria and on JNK activation.…”

Pharmacological Overview of the BGP-15 Chemical Agent as a New Drug Candidate for the Treatment of Symptoms of Metabolic Syndrome

“…This cell line is a suitable in vitro model for the investigation of glucose uptake [29]. To evaluate the effect of BGP-15 on mitochondrial fragmentation, WRL-68, C 2 C 12 , A549 and Sf9 cell cultures were maintained [30]. Mitochondrial ROS production has also been studied on the WRL-68 cell line [24].…”

Enhancing Mitochondrial Health to Treat Hypertension

“…Therefore, therapies oriented to enhance mitochondrial fusion or prevent fission might be beneficial to attenuate hypertension-induced organ damage. Indeed, hydroxylamine derivatives, which activate optic atrophy-1 and promote the fusion of inner mitochondrial membranes, ameliorated lung damage in a murine model of pulmonary arterial hypertension [51]. Recently, treatment with a drug that prevents activation of the mitochondrial fission marker dynamin related protein (DRP)-1 ameliorated vascular remodeling and inflammation in spontaneously hypertensive rats [52], in accordance with previous observations in cardiomyocytes subjected to renal [53] and cardiac [54] reperfusion injury.…”