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PreprintCC BYbioRxiv

AMPK reinforces mitochondrial metabolism and suppresses pathological remodeling in Complex V-deficient cardiomyocytes

  • E. Palacios-Contreras
  • K. an der Brugge
  • J. Fell
  • T. Stephan
  • H. Amedei
  • C. Lenz
  • J. Pesek
  • V. R. Taudte
  • F. Lange
  • S. Jakobs
  • S. Sossalla
  • L. C. Zelarayan
3 more authors
  • A. Cabrera-Orefice
  • L. Cyganek1
  • M. G. Pavez-Giani
  1. 1University Medical Center Goettingen
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Abstract

TMEM70 variants represent the most common nuclear cause of mitochondrial ATP synthase (Complex V) deficiency and are associated with particularly severe cardiac manifestations. Yet, how TMEM70 deficiency disrupts cardiomyocyte metabolic maturation and function remains poorly understood, in part because suitable human disease models are lacking. Here, we model TMEM70-related Complex V deficiency using CRISPR-engineered human induced pluripotent stem cells differentiated into cardiomyocytes. While TMEM70-deficient pluripotent cells retain mitochondrial function, differentiated cardiomyocytes develop reduced mitochondrial membrane potential, impaired respiratory capacity, and pathological remodeling, revealing a differentiation-dependent failure of metabolic maturation. Chronic activation of AMP-activated protein kinase (AMPK) restores mitochondrial respiratory capacity despite persistent Complex V deficiency. Proteomic and metabolomic analyses reveal that AMPK activation in TMEM70-deficient cardiomyocytes reinforces mitochondrial and fatty-acid metabolism while suppressing pathological structural remodeling, accompanied by improved cardiac function. Together, these findings identify AMPK-dependent metabolic remodeling as a state-dependent mechanism of functional rescue in mitochondrial cardiomyopathy.

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Cite

BibTeXRIS
BibTeX
@misc{palacioscontreras2026ampk,
  title = {{AMPK reinforces mitochondrial metabolism and suppresses pathological remodeling in Complex V-deficient cardiomyocytes}},
  author = {E. Palacios-Contreras and K. an der Brugge and J. Fell and T. Stephan and H. Amedei and C. Lenz and J. Pesek and V. R. Taudte and F. Lange and S. Jakobs and S. Sossalla and L. C. Zelarayan and A. Cabrera-Orefice and L. Cyganek and M. G. Pavez-Giani},
  howpublished = {bioRxiv},
  year = {2026},
  month = sep,
  doi = {10.64898/2026.09.14.751384},
  url = {https://www.biorxiv.org/content/10.64898/2026.09.14.751384v1},
  note = {CC BY},
}
RIS
TY  - UNPB
TI  - AMPK reinforces mitochondrial metabolism and suppresses pathological remodeling in Complex V-deficient cardiomyocytes
AU  - E. Palacios-Contreras
AU  - K. an der Brugge
AU  - J. Fell
AU  - T. Stephan
AU  - H. Amedei
AU  - C. Lenz
AU  - J. Pesek
AU  - V. R. Taudte
AU  - F. Lange
AU  - S. Jakobs
AU  - S. Sossalla
AU  - L. C. Zelarayan
AU  - A. Cabrera-Orefice
AU  - L. Cyganek
AU  - M. G. Pavez-Giani
PY  - 2026
DA  - 2026/09/14
PB  - bioRxiv
DO  - 10.64898/2026.09.14.751384
UR  - https://www.biorxiv.org/content/10.64898/2026.09.14.751384v1
AB  - TMEM70 variants represent the most common nuclear cause of mitochondrial ATP synthase (Complex V) deficiency and are associated with particularly severe cardiac manifestations. Yet, how TMEM70 deficiency disrupts cardiomyocyte metabolic maturation and function remains poorly understood, in part because suitable human disease models are lacking. Here, we model TMEM70-related Complex V deficiency using CRISPR-engineered human induced pluripotent stem cells differentiated into cardiomyocytes. While TMEM70-deficient pluripotent cells retain mitochondrial function, differentiated cardiomyocytes develop reduced mitochondrial membrane potential, impaired respiratory capacity, and pathological remodeling, revealing a differentiation-dependent failure of metabolic maturation. Chronic activation of AMP-activated protein kinase (AMPK) restores mitochondrial respiratory capacity despite persistent Complex V deficiency. Proteomic and metabolomic analyses reveal that AMPK activation in TMEM70-deficient cardiomyocytes reinforces mitochondrial and fatty-acid metabolism while suppressing pathological structural remodeling, accompanied by improved cardiac function. Together, these findings identify AMPK-dependent metabolic remodeling as a state-dependent mechanism of functional rescue in mitochondrial cardiomyopathy.
ER  -