Goikoetxea-Usandizaga 2019 MiPschool Coimbra

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Naroa Goikoetxea Usandizaga
Methylation Controlled J protein (MCJ): A therapeutic target in hepatic ischemia and reperfusion injury.

Link: MitoEAGLE

Goikoetxea Usandizaga N, Fernandez-Ramos D, Serrano-Macia M, Cornide ME, Jimenez M, Alfano B, Saenz de Urturi D, Gonzalez-Romero F, Gutierrez-De Juan V, Rodriguez-Iruretagoyena B, Delgado TC, Lopitz-Otsoa F, Barbier-Torres L, Fernandez-Tussy P, Simon J, Martin-Sanz P, Rincon M, Anguita J, Redondo M, Minanbres E, Lu SC, Mato JM, Sabio G, Aspichueta P, Casado M, Martin C, Peralta C, Varela-Rey M, Martinez-Chantar ML (2019)

Event: MiPschool Coimbra 2019

COST Action MitoEAGLE

One of the greatest challenges to overcome in liver transplantation is to reduce the distance between the need for organs and their availability, increasing the use of organs that are currently considered unsuitable for transplantation (from older or steatotic donors). In addition, ischemia reperfusion (IR) injury, a frequent pathological process during liver resection, is a leading cause of post transplantation organ dysfunction. The survival of the patient is clearly determined by the ischemic damage suffered by the organ and by its intrinsic capacity to regenerate [1]. Mitochondria play a key role in liver homeostasis, and a more functional mitochondria induces hepatic regeneration.

Methylation-controlled J protein (MCJ), also known as DnaJC15, is a small protein that belongs to the DnaJ family of co-chaperones. Unlike other DnaJ proteins, MCJ is not soluble, since it contains a transmembrane domain and localizes in the inner mitochondrial membrane (IMM). The recently identified mice ortholog of human MCJ is highly expressed in tissues with active mitochondrial metabolism such as heart, liver and kidney. MCJ interacts with and represses the function of complex I of the ETC, making it the first endogenous inhibitor of complex I. MCJ deletion in vivo results in increased complex I activity, MMP and ATP production, without affecting mitochondrial mass. Indeed, MCJ interferes with the formation of respiratory Super Complex facilitating an efficient transfer of electrons and minimizing ROS production [2]. We therefore present MCJ as a new target to minimize hepatic damage caused by IR injury and enhance the efficiency of liver regeneration during liver resection.

Partial hepatectomies (PHx) and PHx combined with IR injuries were performed in MCJ-KO mice and in WT mice after MCJ silencing.

We firstly validated that MCJ absence increases basal, maximal and ATP-linked respiration in isolated primary hepatocytes from regenerative livers, as well as ATP production and secretion; it also reduces ROS levels significantly 24h after the PHx. We observed that lack of MCJ accelerates liver regeneration 12 hours compared to control, reflected in higher cyclin D1, E, A2 and PCNA expression, along with a significantly higher liver weight/body weight ratio 48 hours after the PHx. Besides, silencing of MCJ mimic the results obtained in MCJ KO mice and it overcomes age related limitations, enhancing regeneration and reducing hepatomegaly in old mice. In the preclinical model of ischemia reperfusion injury, MCJ-KO mice showed lower levels of apoptotic proteins (Cleaved Caspase 3, Cleaved PARP, Bcl-xL) and significantly higher Cyclin D1 expression. When we combined the PHx and IR procedures, MCJ loss increased survival up to 80%, when just the 50% of MCJ-WT mice survived.

In summary, we place MCJ as a potential new target to minimize hepatic damage caused by IR injury and enhance the efficiency of liver regeneration during liver resection, enabling the use of “marginal” organs particularly susceptible to IR injury and unsuitable for transplantation.


Bioblast editor: Plangger M O2k-Network Lab: ES Valencia Casado Pinna M


Labels: MiParea: Respiration, Genetic knockout;overexpression  Pathology: Aging;senescence  Stress:Ischemia-reperfusion, Oxidative stress;RONS  Organism: Mouse  Tissue;cell: Liver  Preparation: Intact cells, Homogenate, Isolated mitochondria 


Coupling state: OXPHOS 

HRR: Oxygraph-2k 


Affiliations and support

Goikoetxea-Usandizaga N(1), Fernández-Ramos D(2), Serrano-Maciá M(1), Cornide ME(3), Jiménez M(3), Alfano B(1), Saenz de Urturi D(4), González-Romero F(4), Gutiérrez-De Juan V(1), Rodríguez-Iruretagoyena B(1), Delgado TC(1), Lopitz-Otsoa F(2), Barbier-Torres L(5), Fernandez-Tussy P(1), Simon J(1), Martín-Sanz P(6), Rincón M(7), Anguita J(8), Redondo M(9), Miñanbres E(9), Lu SC(5), Mato JM(2), Sabio G(10), Aspichueta P(4), Casado M(11), Martin C(12), Peralta C(3), Varela-Rey M(1), Martínez-Chantar ML(1)
  1. CIC bioGUNE, CIBERehd, Liver Disease Lab
  2. CIC bioGUNE, CIBERehd, Liver Metabolism Lab; Derio, Spain
  3. Inst Investigaciones Biomédicas August Pi i Sunyer (IDIBAPS), Liver, Digestive System Metabolism Department, Liver Transplantation Graft Viability Lab, Barcelona, Spain
  4. Univ Basque Country & Biocruces Health Research Inst, Physiology, Fac Medicine Nursing, Leioa & Barakaldo, Spain
  5. Cedars-Sinai Medical Centre, Div Digestive Liver Disease, Los Angeles, United States
  6. Inst Investigaciones Biomédicas (IIB) “Alberto Sols”, CSIC-UAM, Cell Signalling Metabolism Department, Madrid, Spain
  7. Univ Vermont, Depart Medicine Immunobiology, College Medicine, Burlington, United States
  8. CIC bioGUNE, Macrophague Tick Vaccine Lab, Derio, Spain
  9. Marques de Valdecilla Univ Hospital, Cantabria Univ, Santander, Spain
  10. Centro Nacional Investigaciones Cardiovasculares (CNIC), Stress Kinases Diabetes, Cancer Biochemistry, Madrid, Spain
  11. Inst Biomedicina de Valencia, IBV-CSIC, Experimental Metabolic Pathology Dept, Valencia, Spain
  12. Biofisika Inst, Centro Superior Investigaciones Cientificas (CSIC) and Univ Basque Country, Biochemistry, Fac Science Technology, Leioa, Spain. - ngoikoetxea@cicbiogune.es
This work has been founded by Basque Government and MINECO.

References

  1. Zhai Y, Petrowsky H, Hong JC, Busuttil RW, Kupiec-Weglinski JW (2013) Ischaemia-reperfusion injury in liver transplantation – from bench to bedside. Nat Rev Gastroenterol Hetapatol 10:79-89.
  2. Barbier-Torres L, Iruzubieta P, Fernández-Ramos D, Delgado TC, Taibo D, Guitiérrez-de-Juan V, Varela-Rey M, Azkargorta M, Navasa N, Fernández-Tussy P, Zubiete-Franco I, Simon J, Lopitz-Otsoa F, Lachiondo-Ortega S, Crespo J, Masson S, McCain MV, Villa E, Reeves H, Elortza F, Lucena MI, Hernández-Alvarez MI, Zorzano A, Andrade RJ, Lu SC, Mato JM, Anguita J, Rincón M, Martínez-Chantar ML (2017) The mitochondrial negative regulator MCJ is a therapeutic target for APAP induced liver injury. Nat Commun 8:2068.