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NNT deficiency alters cardiac structure and function without impairing mitochondrial bioenergetics in aged mice

Dalla Costa, Ana P. ; Navarro, Claudia D.C. ; Siqueira-Santos, Edilene S. ; Velasco, Rafaela Q.S. ; Rosada, João V.F. ; Salgado, Andréia R. ; Demolin, Daniele M.R. ; Passos, Luiz A.C. ; Vercesi, Anibal E. and Francisco, Annelise LU orcid , et al. (2025) In Redox Biology 88.
Abstract

Proton-translocating NAD(P)+ transhydrogenase (NNT) is highly expressed in cardiac tissue, where it physiologically supports mitochondrial NADPH production. However, under certain pathological conditions, NNT may shift toward consuming the mitochondrial NADPH pool. Although NNT has been implicated in redox homeostasis, its contribution to cardiac function during aging remains uncertain. In this study, we assessed cardiac morphology and function, as well as mitochondrial bioenergetics and Ca2+ handling, in NNT-deficient ( Nnt −/− ) mice and congenic wild-type controls ( Nnt +/+ ) at adult (5 months), middle (12 months), and older (23 months) ages. NNT-deficient mice developed age-related... (More)

Proton-translocating NAD(P)+ transhydrogenase (NNT) is highly expressed in cardiac tissue, where it physiologically supports mitochondrial NADPH production. However, under certain pathological conditions, NNT may shift toward consuming the mitochondrial NADPH pool. Although NNT has been implicated in redox homeostasis, its contribution to cardiac function during aging remains uncertain. In this study, we assessed cardiac morphology and function, as well as mitochondrial bioenergetics and Ca2+ handling, in NNT-deficient ( Nnt −/− ) mice and congenic wild-type controls ( Nnt +/+ ) at adult (5 months), middle (12 months), and older (23 months) ages. NNT-deficient mice developed age-related cardiac hypertrophy, along with a moderately reduced ejection fraction and fractional shortening at older ages, suggesting left ventricular dysfunction. These changes were associated with increased mitochondrial H2O2 release under specific conditions, whereas mitochondrial bioenergetic parameters and Ca2+ retention capacity remained largely unaffected by the Nnt genotype at all ages. Our findings indicate that NNT plays a protective role in the aging heart by maintaining redox balance and that NNT deficiency may contribute to late-onset cardiac dysfunction without causing overt mitochondrial bioenergetic failure. These results provide insight into the potential cardiac consequences of pathogenic NNT variants in humans.

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publication status
published
subject
keywords
Aging, C57BL/6J mouse, Cardiac function, Mitochondrial bioenergetics, Nicotinamide nucleotide transhydrogenase (NNT), Nnt mutation
in
Redox Biology
volume
88
article number
103935
publisher
Elsevier
external identifiers
  • scopus:105022797026
  • pmid:41274037
ISSN
2213-2317
DOI
10.1016/j.redox.2025.103935
language
English
LU publication?
yes
id
d4ddb45a-48ac-42f2-9db0-276f3643492f
date added to LUP
2026-01-14 14:58:37
date last changed
2026-01-14 14:59:05
@article{d4ddb45a-48ac-42f2-9db0-276f3643492f,
  abstract     = {{<p>Proton-translocating NAD(P)<sup>+</sup> transhydrogenase (NNT) is highly expressed in cardiac tissue, where it physiologically supports mitochondrial NADPH production. However, under certain pathological conditions, NNT may shift toward consuming the mitochondrial NADPH pool. Although NNT has been implicated in redox homeostasis, its contribution to cardiac function during aging remains uncertain. In this study, we assessed cardiac morphology and function, as well as mitochondrial bioenergetics and Ca<sup>2+</sup> handling, in NNT-deficient ( Nnt <sup> −/− </sup>) mice and congenic wild-type controls ( Nnt <sup> +/+ </sup>) at adult (5 months), middle (12 months), and older (23 months) ages. NNT-deficient mice developed age-related cardiac hypertrophy, along with a moderately reduced ejection fraction and fractional shortening at older ages, suggesting left ventricular dysfunction. These changes were associated with increased mitochondrial H<sub>2</sub>O<sub>2</sub> release under specific conditions, whereas mitochondrial bioenergetic parameters and Ca<sup>2+</sup> retention capacity remained largely unaffected by the Nnt genotype at all ages. Our findings indicate that NNT plays a protective role in the aging heart by maintaining redox balance and that NNT deficiency may contribute to late-onset cardiac dysfunction without causing overt mitochondrial bioenergetic failure. These results provide insight into the potential cardiac consequences of pathogenic NNT variants in humans.</p>}},
  author       = {{Dalla Costa, Ana P. and Navarro, Claudia D.C. and Siqueira-Santos, Edilene S. and Velasco, Rafaela Q.S. and Rosada, João V.F. and Salgado, Andréia R. and Demolin, Daniele M.R. and Passos, Luiz A.C. and Vercesi, Anibal E. and Francisco, Annelise and Castilho, Roger F.}},
  issn         = {{2213-2317}},
  keywords     = {{Aging; C57BL/6J mouse; Cardiac function; Mitochondrial bioenergetics; Nicotinamide nucleotide transhydrogenase (NNT); Nnt mutation}},
  language     = {{eng}},
  publisher    = {{Elsevier}},
  series       = {{Redox Biology}},
  title        = {{NNT deficiency alters cardiac structure and function without impairing mitochondrial bioenergetics in aged mice}},
  url          = {{http://dx.doi.org/10.1016/j.redox.2025.103935}},
  doi          = {{10.1016/j.redox.2025.103935}},
  volume       = {{88}},
  year         = {{2025}},
}