MnTE-2-PyP protects fibroblast mitochondria from hyperglycemia and radiation exposure

Arpita Chatterjee; Isin T Sakallioglu; Divya Murthy; Elizabeth A Kosmacek; Pankaj K Singh; J Tyson McDonald; Robert Powers; Rebecca E Oberley-Deegan

doi:10.1016/j.redox.2022.102301

MnTE-2-PyP protects fibroblast mitochondria from hyperglycemia and radiation exposure

Redox Biol. 2022 Jun:52:102301. doi: 10.1016/j.redox.2022.102301. Epub 2022 Mar 24.

Authors

Arpita Chatterjee¹, Isin T Sakallioglu², Divya Murthy³, Elizabeth A Kosmacek¹, Pankaj K Singh³, J Tyson McDonald⁴, Robert Powers⁵, Rebecca E Oberley-Deegan⁶

Affiliations

¹ Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA.
² Department of Chemistry, University of Nebraska-Lincoln, Lincoln, NE, 68588-0304, USA.
³ The Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, 68198, USA.
⁴ Department of Physics & Cancer Research Center, Hampton University, Hampton, VA, 23668, USA.
⁵ Department of Chemistry, University of Nebraska-Lincoln, Lincoln, NE, 68588-0304, USA; Nebraska Center for Integrated Biomolecular Communication, University of Nebraska-Lincoln, Lincoln, NE, 68588-0304, USA.
⁶ Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA. Electronic address: becky.deegan@unmc.edu.

Abstract

Radiation is a common anticancer therapy for prostate cancer, which transforms tumor-associated normal fibroblasts to myofibroblasts, resulting in fibrosis. Oxidative stress caused by radiation-mediated mitochondrial damage is one of the major contributors to fibrosis. As diabetics are oxidatively stressed, radiation-mediated reactive oxygen species cause severe treatment failure, treatment-related side effects, and significantly reduced survival for diabetic prostate cancer patients as compared to non-diabetic prostate cancer patients. Hyperglycemia and enhanced mitochondrial damage significantly contribute to oxidative damage and disease progression after radiation therapy among diabetic prostate cancer patients. Therefore, reduction of mitochondrial damage in normal prostate fibroblasts after radiation should improve the overall clinical state of diabetic prostate cancer patients. We previously reported that MnTE-2-PyP, a manganese porphyrin, reduces oxidative damage in irradiated hyperglycemic prostate fibroblasts by scavenging superoxide and activating NRF2. In the current study, we have investigated the potential role of MnTE-2-PyP to protect mitochondrial health in irradiated hyperglycemic prostate fibroblasts. This study revealed that hyperglycemia and radiation increased mitochondrial ROS via blocking the mitochondrial electron transport chain, altered mitochondrial dynamics, and reduced mitochondrial biogenesis. Increased mitochondrial damage preceeded an increase in myofibroblast differentiation. MnTE-2-PyP reduced myofibroblast differentiation, improved mitochondrial health by releasing the block on the mitochondrial electron transport chain, enhanced ATP production efficiency, and restored mitochondrial dynamics and metabolism in the irradiated-hyperglycemic prostate fibroblasts. Therefore, we are proposing that one of the mechanisms that MnTE-2-PyP protects prostate fibroblasts from irradiation and hyperglycemia-mediated damage is by protecting the mitochondrial health in diabetic prostate cancer patients.

Keywords: Diabetes; Fibroblast metabolism; Manganese porphyrin; Mitochondria; ROS; Radiation.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Diabetes Mellitus* / metabolism
Fibroblasts / metabolism
Fibrosis
Humans
Hyperglycemia* / metabolism
Male
Metalloporphyrins*
Mitochondria / metabolism
Prostatic Neoplasms* / metabolism
Prostatic Neoplasms* / radiotherapy
Radiation Exposure*

Substances

Metalloporphyrins
manganese tetrakis-(N-ethyl-2 pyridyl) porphyrin