Promising Strategy of mPTP Modulation in Cancer Therapy - An Emerging Progress and Future Insight

Sep 24, 2026

Cancer remains a major global health concern, with cancer development posing a critical public health challenge. Mitochondrial dysfunction is highlighted as a hallmark of cancer cells, and mitochondrial membrane permeabilization is central to apoptosis-mediated death. Under mitochondrial calcium overload driven by oxidative stress, formation and opening of the mitochondrial permeability transition pore (mPTP) enables exchange of solutes and proteins up to 1.5 kDa. mPTP regulates apoptosis, linked to hexokinase II and cytochrome c release, and contributes to the pathogenesis of multiple cancers through complex structure and regulation. This review summarizes mPTP mechanisms and discusses development of mPTP-targeting therapeutic molecules.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages26

Reading Time1 h 6 min

AccessFree to download

Abstract

Keywords

1. Introduction

Mitochondria and intrinsic apoptosis

MOMP and mitochondrial permeability transition

Role of calcium overload and nonspecific permeabilization

Figure 1 - Schematic representation of mPTP junction states

Review Promising Strategy of mPTP Modulation in Cancer Therapy: An Emerging Progress and Future Insight Mohammad Waseem 1 and Bi-Dar Wang 1,2, * Citation: Waseem, M.; Wang, B.-D. Promising Strategy of mPTP Modulation in Cancer Therapy: An Emerging Progress and Future Insight. Int. J. Mol. Sci. 2023, 24, 5564 . [https://doi.org/10.3390/](https://doi.org/10.3390/)[ ](https://doi.org/10.3390/)ijms24065564 Academic Editors: Elena Levantini and Daniela Sanchez Bass±res Received: 7 February 2023 Revised: 4 March 2023 Accepted: 7 March 2023 Published: 14 March 2023 Copyright: © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ([https://](https://)[ ](https://)[creativecommons.org/licenses/by/](creativecommons.org/licenses/by/)[ ](creativecommons.org/licenses/by/)[4.0/](4.0/)) . 1 Department of Pharmaceutical Sciences, School of Pharmacy and Health Professions, University of Maryland Eastern Shore, Princess Anne, MD 21853, USA; [mwaseem@umes.edu](mwaseem@umes.edu) 2 Hormone Related Cancers Program, University of Maryland Greenebaum Comprehensive Cancer Center, Baltimore, MD 21201, USA * [Correspondence: bwang@umes.edu](Correspondence: bwang@umes.edu); Tel.: +1-410-621-2240; Fax: +1-410-651-8394 Abstract: Cancer has been progressively a major global health concern. With this developing global concern, cancer determent is one of the most signiﬁcant public health challenges of this era. To date, the scientiﬁc community undoubtedly highlights mitochondrial dysfunction as a hallmark of cancer cells. Permeabilization of the mitochondrial membranes has been implicated as the most considerable footprint in apoptosis-mediated cancer cell death. Under the condition of mitochondrial calcium overload, exclusively mediated by oxidative stress, an opening of a nonspeciﬁc channel with a well-deﬁned diameter in mitochondrial membrane allows free exchange between the mitochondrial matrix and the extra mitochondrial cytosol of solutes and proteins up to 1.5 kDa. Such a channel/nonspeciﬁc pore is recognized as the mitochondrial permeability transition pore (mPTP) . mPTP has been established for regulating apoptosis-mediated cancer cell death. It has been evident that mPTP is critically linked with the glycolytic enzyme hexokinase II to defend cellular death and reduce cytochrome c release. However, elevated mitochondrial Ca2+ loading, oxidative stress, and mitochondrial depolarization are critical factors leading to mPTP opening/activation. Although the exact mechanism underlying mPTP-mediated cell death remains elusive, mPTP-mediated apoptosis machinery has been considered as an important clamp and plays a critical role in the pathogenesis of several types of cancers. In this review, we focus on structure and regulation of the mPTP complex-mediated apoptosis mechanisms and follow with a comprehensive discussion addressing the development of novel mPTP-targeting drugs/molecules in cancer treatment. Keywords: mPTP; therapeutic targets; mPTP-mediated apoptosis; MOMP; oxidative stress 1. Introduction Mitochondria are considered as intracellular organelles crucial for energy generation and are also involved in several kinds of cellular damage and/or death including necrosis, apoptosis, and other impaired mechanisms via mitochondrial outer membrane permeabilization (MOMP) [1] . Mitochondria have been revealed to mediate the intrinsic apoptotic pathway provoked by the cytotoxic potency of different kinds of chemotherapeutic molecules [2] . These mitochondria-mediated intrinsic machinery could be triggered by different stimuli, such as high contents of cytoplasmic Ca2+, overproduction of reactive oxygen species (ROS), and other environmental factors such as UV damage [3–5] . Such stimuli activate apoptotic cascade, increase apoptotic protein expression, promote release of cytochrome c (Cyt

FAQs

What is mPTP and why is it important in cancer therapy?

mPTP is a mitochondrial permeability transition pore whose opening is implicated in apoptosis-mediated cancer cell death. It is linked to mitochondrial calcium overload, oxidative stress, and downstream apoptotic machinery, making it a potential therapeutic target.

How do oxidative stress and calcium overload contribute to mPTP activation?

The review describes mitochondrial calcium overload mediated by oxidative stress as a condition that leads to mPTP opening/activation. These factors drive permeability changes in mitochondrial membranes and promote apoptotic processes.

Which relationship does the article highlight between mPTP and hexokinase II?

mPTP is described as critically linked with hexokinase II. This linkage is presented as a defense mechanism that helps regulate cellular death and reduce cytochrome c release.

Sep 24, 2026

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