Biology subjects

Finck, B. N.

Publications and source records attributed to Finck, B. N..

3 recordsLinked to original sources

bioRxiv2020

Ketogenic Diet Prevents Heart Failure from Defective Mitochondrial Pyruvate Metabolism

The myocardium is metabolically flexible and can use fatty acids, glucose, lactate/pyruvate, ketones, or amino acids to fuel mechanical work. However, impaired metabolic flexibility is associated with cardiac dysfunction in conditions including diabetes and heart failure. The mitochondrial pyruvate carrier (MPC) is required for pyruvate metabolism and is composed of a hetero-oligomer of two proteins known as MPC1 and MPC2. Interestingly, MPC1 and MPC2 expression is downregulated in failing human hearts and in a mouse model of heart failure. Mice with cardiac-specific deletion of MPC2 (CS-MPC2-/-) exhibited loss of both MPC2 and MPC1 proteins and reduced pyruvate-stimulated mitochondrial respiration. CS-MPC2-/- mice exhibited normal cardiac size and function at 6-weeks old, but progressively developed cardiac dilation and contractile dysfunction thereafter. Feeding CS-MPC2-/- mice a ketogenic diet (KD) completely prevented or reversed the cardiac remodeling and dysfunction. Other diets with higher fat content and enough carbohydrate to limit ketosis also improved heart failure in CS-MPC2-/- mice, but direct ketone body provisioning provided only minor improvements in cardiac remodeling. Finally, KD was also able to prevent further remodeling in an ischemic, pressure-overload mouse model of heart failure. In conclusion, loss of mitochondrial pyruvate utilization leads to dilated cardiomyopathy that can be corrected by a ketogenic diet.

physiology↗

bioRxiv2019

Lipin-1 contributes to IL-4 mediated macrophage polarization

Macrophage responses contribute to a diverse array of pathologies ranging from infectious disease to sterile inflammation. Polarization of macrophages determines their cellular function within biological processes. Lipin-1 is a phosphatidic acid phosphatase in which its enzymatic activity contributes to macrophage pro-inflammatory responses. Lipin-1 also possesses transcriptional co-regulator activity and whether this activity is required for macrophage polarization is unknown. Using mice that lack only lipin-1 enzymatic activity or both enzymatic and transcriptional coregulator activities from myeloid cells, we investigated the contribution of lipin-1 transcriptional co-regulator function towards macrophage wound healing polarization. Macrophages lacking both lipin-1 activities did elicit IL-4 mediated gene expression to levels seen in either wild-type or lipin-1 enzymatically deficient macrophages. Furthermore, we provide evidence that the lack of myeloid-associated lipin-1 transcriptional co-regulator activity leads to impaired full thickness excisional wound healing. Our study demonstrates that lipin-1 transcriptional co-regulatory activity contributes to macrophage polarization and the macrophage contribution to wound healing in vivo.

immunology↗

bioRxiv2019

NADPH and glutathione redox link TCA cycle activity to endoplasmic reticulum stress

Endoplasmic reticulum (ER) stress is associated with dysregulated metabolism, but little is known about how the ER responds to metabolic activity. Here, working primarily in mouse hepatocytes, we show that decreasing the availability of substrate for the TCA cycle diminished NADPH production and attenuated ER stress in a manner that depended on glutathione oxidation. ER stress was also alleviated by impairing either TCA-dependent NADPH production or Glutathione Reductase. Conversely, stimulating TCA activity favored NADPH production, glutathione reduction, and ER stress. Validating these findings, we show that deletion of the mitochondrial pyruvate carrier, which is known to decrease TCA cycle activity and protect the liver from diet-induced injury, also diminished NADPH, elevated glutathione oxidation, and alleviated ER stress. These results provide independent genetic evidence that mitochondrial oxidative metabolism is linked to ER homeostasis. Our results demonstrate a novel pathway of communication between mitochondria and the ER, through relay of redox metabolites.

cell biology↗