at the CNIC

Tag: mitochondria

Cell identity and nucleo-mitochondrial genetic context modulate OXPHOS performance and determine somatic heteroplasmy dynamics

Ana Victoria Lechuga-Vieco, Ana Latorre-Pellicer, Iain G. Johnston, Gennaro Prota, Uzi Gileadi, Raquel Justo-Méndez, Rebeca Acín-Pérez, Raquel Martínez-de-Mena, Jose María Fernández-Toro, Daniel Jimenez-Blasco, Alfonso Mora, Jose A. Nicolás-Ávila, Demetrio J. Santiago, Silvia G. Priori, Juan Pedro Bolaños, Guadalupe Sabio, Luis Miguel Criado, Jesús Ruíz-Cabello, Vincenzo Cerundolo, Nick S. Jones, José Antonio Enríquez.

Heteroplasmy, multiple variants of mitochondrial DNA (mtDNA) in the same cytoplasm, may be naturally generated by mutations but is counteracted by a genetic mtDNA bottleneck during oocyte development.

Mitochondria (Image: Alfonso Mora).

Engineered heteroplasmic mice with nonpathological mtDNA variants reveal a nonrandom tissue-specific mtDNA segregation pattern, with few tissues that do not show segregation. The driving force for this dynamic complex pattern has remained unexplained for decades, challenging our understanding of this fundamental biological problem and hindering clinical planning for inherited diseases.

Here, we demonstrate that the nonrandom mtDNA segregation is an intracellular process based on organelle selection. This cell type–specific decision arises jointly from the impact of mtDNA haplotypes on the oxidative phosphorylation (OXPHOS) system and the cell metabolic requirements and is strongly sensitive to the nuclear context and to environmental cues.

Protein kinase D1 deletion in adipocytes enhances energy dissipation and protects against adiposity

Mona C. Löffler, Alexander E. Mayer, Jonathan Trujillo Viera, Angel Loza Valdes, Rabih El‐Merahbi, Carsten P. Ade, Till Karwen, Werner Schmitz, Anja Slotta, Manuela Erk, Sudha Janaki‐Raman, Nuria Matesanz, Jorge L. Torres, Miguel Marcos, Guadalupe Sabio, Martin Eilers, Almut Schulze, Grzegorz Sumara.

Nutrient overload in combination with decreased energy dissipation promotes obesity and diabetes. Obesity results in a hormonal imbalance, which among others activates G protein‐coupled receptors utilizing diacylglycerol (DAG) as secondary messenger. Protein kinase D1 (PKD1) is a DAG effector, which integrates multiple nutritional and hormonal inputs, but its physiological role in adipocytes is unknown.

Correlation between PKD1 and HOMA‐IR

Correlation between PKD1 expression and HOMA‐IR levels in human sWAT (Image: Nuria Matesanz).

Here, we show that PKD1 promotes lipogenesis and suppresses mitochondrial fragmentation, biogenesis, respiration, and energy dissipation in an AMP‐activated protein kinase (AMPK)‐dependent manner. Moreover, mice lacking PKD1 in adipocytes are resistant to diet‐induced obesity due to elevated energy expenditure. Beiging of adipocytes promotes energy expenditure and counteracts obesity. Consistently, deletion of PKD1 promotes expression of the β3‐adrenergic receptor (ADRB3) in a CCAAT/enhancer binding protein (C/EBP)‐α‐ and δ‐dependent manner, which leads to the elevated expression of beige markers in adipocytes and subcutaneous adipose tissue. Finally, deletion of PKD1 in adipocytes improves insulin sensitivity and ameliorates liver steatosis.

Our results showed that p38δ is activated in BAT by cold exposure, and lack of this kinase specifically in adipose tissue (p38δFab-KO) resulted in overweight together with reduced energy expenditure and lower body and skin surface temperature in the BAT region. These observations indicate that p38α probably blocks BAT thermogenesis through p38δ inhibition. Consistent with the results obtained in animals, p38α was reduced in visceral and subcutaneous adipose tissue of subjects with obesity and was inversely correlated with body mass index (BMI).

Thus, depletion of PKD1 in adipocytes increases energy dissipation by several complementary mechanisms and might represent an attractive strategy to treat obesity and its related complications.

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