Mitochondria have various cellular functions, including ATP synthesis, calcium homeostasis, cell senescence, and death. Mitochondrial dysfunction has been identified in a variety of disorders correlated with human health. Among the many underlying mechanisms of mitochondrial dysfunction, the opening up of the mitochondrial permeability transition pore (mPTP) is one that has drawn increasing interest in recent years. It plays an important role in apoptosis and necrosis; however, the molecular structure and function of the mPTP have still not been fully elucidated. In recent years, the abnormal opening up of the mPTP has been implicated in the development and pathogenesis of diverse diseases including ischemia/reperfusion injury (IRI), neurodegenerative disorders, tumors, and chronic obstructive pulmonary disease (COPD). This review provides a systematic introduction to the possible molecular makeup of the mPTP and summarizes the mitochondrial dysfunction-correlated diseases and highlights possible underlying mechanisms. Since the mPTP is an important target in mitochondrial dysfunction, this review also summarizes potential treatments, which may be used to inhibit pore opening up via the molecules composing mPTP complexes, thus suppressing the progression of mitochondrial dysfunction-related diseases.

Recent progress in the use of mitochondrial membrane permeability transition pore in mitochondrial dysfunction-related disease therapies

Few translocator protein (TSPO) radioligands have been rapidly translated into human clinical research with the enthusiasm of F-GE180. Within two years from the publication of the first kinetic analyses in humans [1, 2], four clinical studies in patients with brain tumors [3, 4] and multiple sclerosis [5, 6], at least three case-reports [7–9], and one editorial praising the “definitely superior” imaging qualities of F-GE180 [10] appeared in the literature. Two advantages are attributed to F-GE180 by its proponents:

Anatomy of 18F-GE180, a failed radioligand for the TSPO protein.

Dear Sir, We read with interest the recently published letter by Zanotti-Fregonara et al. [1] that very critically discusses the characteristics of F-GE180 as a PET tracer for the 18-kDa mitochondrial translocator protein (TSPO) in human brain. This follows a previously published and rather similar letter and thus offers little information that is substantially new [2]. The main hypotheses of Zanotti-Fregonara et al. [1] are still that

/pdf/in-response-to-anatomy-of-18f-ge180-a-failed-radioligand-for-3txxzs38ao.pdf

In response to: Anatomy of 18F-GE180, a failed radioligand for the TSPO protein.

Progressive multifocal leukoencephalopathy (PML) is a severe infection of the CNS caused by the polyomavirus JC that can occur in multiple sclerosis patients treated with natalizumab. Clinical management of patients with natalizumab-associated PML is challenging not least because current imaging tools for the early detection, longitudinal monitoring and differential diagnosis of PML lesions are limited. Here we evaluate whether translocator protein (TSPO) PET imaging can be applied to monitor the inflammatory activity of PML lesions over time and differentiate them from multiple sclerosis lesions. For this monocentre pilot study we followed eight patients with natalizumab-associated PML with PET imaging using the TSPO radioligand 18F-GE-180 combined with frequent 3 T MRI. In addition we compared TSPO PET signals in PML lesions with the signal pattern of multiple sclerosis lesions from 17 independent multiple sclerosis patients. We evaluated the standardized uptake value ratio as well as the morphometry of the TSPO uptake for putative PML and multiple sclerosis lesions areas compared to a radiologically unaffected pseudo-reference region in the cerebrum. Furthermore, TSPO expression in situ was immunohistochemically verified by determining the density and cellular identity of TSPO-expressing cells in brain sections from four patients with early natalizumab-associated PML as well as five patients with other forms of PML and six patients with inflammatory demyelinating CNS lesions (clinically isolated syndrome/multiple sclerosis). Histological analysis revealed a reticular accumulation of TSPO expressing phagocytes in PML lesions, while such phagocytes showed a more homogeneous distribution in putative multiple sclerosis lesions. TSPO PET imaging showed an enhanced tracer uptake in natalizumab-associated PML lesions that was present from the early to the chronic stages (up to 52 months after PML diagnosis). While gadolinium enhancement on MRI rapidly declined to baseline levels, TSPO tracer uptake followed a slow one phase decay curve. A TSPO-based 3D diagnostic matrix taking into account the uptake levels as well as the shape and texture of the TSPO signal differentiated >96% of PML and multiple sclerosis lesions. Indeed, treatment with rituximab after natalizumab-associated PML in three patients did not affect tracer uptake in the assigned PML lesions but reverted tracer uptake to baseline in the assigned active multiple sclerosis lesions. Taken together our study suggests that TSPO PET imaging can reveal CNS inflammation in natalizumab-associated PML. TSPO PET may facilitate longitudinal monitoring of disease activity and help to distinguish recurrent multiple sclerosis activity from PML progression.

TSPO PET imaging of natalizumab-associated progressive multifocal leukoencephalopathy.

TSPO PET, tumour grading and molecular genetics in histologically verified glioma: a correlative 18F-GE-180 PET study

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TSPO PET, tumour grading and molecular genetics in histologically verified glioma: a correlative 18F-GE-180 PET study