FUNDC1 interacts with FBXL2 to govern mitochondrial integrity and cardiac function through an IP3R3-dependent manner in obesity

Defective mitophagy is causally linked to obesity complications. Here, we identified an interaction between mitophagy protein FUNDC1 (FUN14 domain containing 1) and receptor subunit of human SCF (SKP1/cullin/F-box protein) ubiquitin ligase complex FBXL2 as a gatekeeper for mitochondrial Ca2+ homeostasis through degradation of IP3R3 (inositol 1,4,5-trisphosphate receptor type 3). Loss of FUNDC1 in FUNDC1−/− mice accentuated high-fat diet–induced cardiac remodeling, functional and mitochondrial anomalies, cell death, rise in IP3R3, and Ca2+ overload. Mass spectrometry and co-immunoprecipitation analyses revealed an interaction between FUNDC1 and FBXL2. Truncated mutants of Fbox (Delta-F-box) disengaged FBXL2 interaction with FUNDC1. Activation or transfection of FBXL2, inhibition of IP3R3 alleviated, whereas disruption of FBXL2 localization sensitized lipotoxicity-induced cardiac damage. FUNDC1 deficiency accelerated and decelerated palmitic acid–induced degradation of FBXL2 and IP3R3, respectively. Our data suggest an essential role for interaction between FUNDC1 and FBXL2 in preserving mitochondrial Ca2+ homeostasis and cardiac function in obese hearts.

Mitophagy, Mitochondrial Dynamics, and Homeostasis in Cardiovascular Aging

Biological aging is an inevitable and independent risk factor for a wide array of chronic diseases including cardiovascular and metabolic diseases. Ample evidence has established a pivotal role for interrupted mitochondrial homeostasis in the onset and development of aging-related cardiovascular anomalies. A number of culprit factors have been suggested in aging-associated mitochondrial anomalies including oxidative stress, lipid toxicity, telomere shortening, metabolic disturbance, and DNA damage, with recent findings revealing a likely role for compromised mitochondrial dynamics and mitochondrial quality control machinery such as autophagy. Mitochondria undergo consistent fusion and fission, which are crucial for mitochondrial homeostasis and energy adaptation. Autophagy, in particular, mitochondria-selective autophagy, namely, mitophagy, refers to a highly conservative cellular process to degrade and clear long-lived or damaged cellular organelles including mitochondria, the function of which gradually deteriorates with increased age. Mitochondrial homeostasis could be achieved through a cascade of independent but closely related processes including fusion, fission, mitophagy, and mitochondrial biogenesis. With improved health care and increased human longevity, the ever-rising aging society has imposed a high cardiovascular disease prevalence. It is thus imperative to understand the role of mitochondrial homeostasis in the regulation of lifespan and healthspan. Targeting mitochondrial homeostasis should offer promising novel therapeutic strategies against aging-related complications, particularly cardiovascular diseases.

Mitochondrial Changes in Cholestasis

Alterations of liver cell mitochondria represent pathologic phenomenon of a fundamental nature. Mitochondrial anomalies have been often described in association with cholestasis. In attempt to determine whether a given pattern of mitochondrial alteration has any correlation with the cause of cholestasis, liver biopsies were examined from 38 patients showing :a. extrahepatic cholestasis due to complete or partial extrahepatic biliary obstruction (8 cases proven at operation)b. intrahepatic cholestasis due to drugs (9 cases), viral hepatitis (6 cases) and alcoholic cirrhosis (15 cases).Mitochondria exhibiting ultrastructural changes due to aging or to the ‘wear and teart’ processes were not considered. In this study, the only profound and most prominent mitochondrial deformation was reported on basis of their common occurrence in randomly examined sections.