Pallotta 2022 Abstract Bioblast

P08. Pallotta Maria Luigia (2022) NAD(P)+/NAD(P)H pool and the art of mitochondrial survival. Bioblast 2022: BEC Inaugural Conference. In: https://doi.org/10.26124/bec:2022-0001

Link: Bioblast 2022: BEC Inaugural Conference

Pallotta Maria Luigia (2022)

Event: Bioblast 2022

Shift in energy metabolism offers immediate potential for intervention and thereby control of entire biochemical networks by identifying and targeting key control points both in physiological and pathological issues. Increasing evidence suggests that the pyridine nucleotide NAD(P)⁺ has many more extensive biological functions than its classical role in energy metabolism. Hundreds of enzymes that catalyze substrate oxidation use coenzyme NAD(P)⁺. Thus it plays a key role in various biological processes such as aging, oxidative stress, epigenetics, immunological response, cell death, and much more.

In 2007 Sinclair’ group [1] referred to the ability of mitochondria to dictate cell survival as “mitochondrial oasis effect” which states that the energetic and NAD(P)⁺ content of mitochondria determines cell survival in face of genotoxic stress (i.e. DNA damage). Still not everything is clear about NAD(P)⁺ biosynthesis in mitochondria. However, de novo and salvage pathways contribute to the biosynthesis of NAD(P)⁺ in all organisms and both converge at the transfer of nicotinamide mononucleotide (NMN) or nicotinic acid mononucleotide (NaMN) on to the adenylyl group of ATP under diphosphate release (NMN+ATP↔NAD⁺+PPi). Given that NMN is a potent inhibitor of the NAD-dependent DNA ligase, nicotinamide mononucleotide adenylyltransferase (NMNAT) activity would scavenge NMN, ensuring at the same time NAD⁺ supply to the ligase reaction. Thus, NMN was added to different eukaryotic cells bioenergetically active (from yeast, plant, and mammalian cancer cells). Mitochondria were prepared starting from cells grown aerobically and analysed according to Pallotta et al (2004) [2]. NAD(P)⁺ biosynthesis was tested by HPLC and spectroscopically [3].

Thus, our results suggest, that mitochondria can increase NAD(P)⁺ content, probably via NMNAT and NADKinase and this “core” mitochondrial NAD(P)⁺ pathway should be studied further — i.e. its regulation with a cocktail of ad hoc inhibitors — as a basis for future biotechnological applications and biomedicine studies in treating disorders with perturbed NAD(P)⁺ supply or homeostasis (viz neurological, immunological and metabolic clinically oriented studies).

1. Yang H, Yang T, Baur JA, Perez E, Matsui T, Carmona JJ, Lamming DW, Souza-Pinto NC, Bohr VA, Rosenzweig A, de Cabo R, Sauve AA, Sinclair DA (2007) Nutrient-sensitive mitochondrial NAD⁺ levels dictate cell survival. https://doi.org/doi:10.1016/j.cell.2007.07.035
2. Pallotta ML, Valenti D, Iacovino M, Passarella S (2004) Two separate pathways for d-lactate oxidation by Saccharomyces cerevisiae mitochondria which differ in energy production and carrier involvement. https://doi.org/doi:10.1016/j.bbabio.2003.10.008
3. Di Martino C, Pallotta ML (2011) Mitochondria-localized NAD biosynthesis by nicotinamide mononucleotide adenylyltransferase in Jerusalem artichoke (Helianthus tuberosus L.) heterotrophic tissues. https://doi.org/doi:10.1007/s00425-011-1428-6

• Keywords: bioenergetics, NAD(P)⁺/NAD(P)H+[H⁺], mitochondrial pool, cellular homeostasis, DNA damage, nicotinamide mononucleotide (NMN) • Bioblast editor: Gnaiger E

Affiliation

Dept Medicine and Health Sciences, Molise University, 86100 Campobasso, IT - [email protected]

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