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Vitamin A depletion causes oxidative stress, mitochondrial dysfunction, and PARP-1-dependent energy deprivation

Haw-Jyh Chiu^*, Donald A. Fischman and Ulrich Hammerling^*,1

^* Memorial Sloan-Kettering Cancer Center, Immunology Program, New York, New York, USA; and

Department of Cell and Developmental Biology, Weill Medical College of Cornell University, New York, New York, USA

¹ Correspondence: Ulrich Hammerling, Memorial Sloan-Kettering Cancer Center, Immunology Program, 1275 York Ave., New York, NY 10065, USA. E-mail: u-hammerling{at}ski.mskcc.org

A significant unresolved question is how vitamin A deprivation causes, and why retinoic acid fails to reverse, immunodeficiency. When depleted of vitamin A, T cells undergo programmed cell death (PCD), which is enhanced by the natural competitor of retinol, anhydroretinol. PCD does not happen by apoptosis, despite the occurrence of shared early events, including mitochondrial membrane depolarization, permeability transition pore opening, and cytochrome c release. It also lacks caspase-3 activation, chromatin condensation, and endonuclease-mediated DNA degradation, hallmarks of apoptosis. PCD following vitamin A deprivation exhibits increased production of reactive oxygen species (ROS), drastic reductions in ATP and NAD⁺ levels, and activation of poly-(ADP-ribose) polymerase (PARP) -1. These latter steps are causative because neutralizing ROS, imposing hypoxic conditions, or inhibiting PARP-1 by genetic or pharmacologic approaches prevents energy depletion and PCD. The data highlight a novel regulatory role of vitamin A in mitochondrial energy homeostasis.—Chiu, H.-J., Fischman, D. A., Hammerling, U. Vitamin A depletion causes oxidative stress, mitochondrial dysfunction, and PARP-1-dependent energy deprivation.

Key Words: lymphocytes • mitochondrion • reactive oxygen species • bioenergetics