Activated peroxisomal fatty acid metabolism improves cardiac recovery in ischemia-reperfusion

Abstract

Depressed oxidation of long chain fatty acids (LCFA) in heart ischemia leads to acute accumulation of LCFA metabolites that impair the functioning of the mitochondria. We hypothesized that reduced activity of carnitine palmitoyltransferase-I (CPT-I) might activate peroxisomal LCFA oxidation and protect mitochondrial function in ischemia and reperfusion. In the present study, despite the long-term threefold reduction in L-carnitine content by 3-(2,2,2-trimethylhydrazinium)-propionate, the uptake and oxidation rates of LCFA in the heart in normoxia were not significantly influenced. The significant increase in PPARα and PGC1α nuclear content, observed in this study, were followed by increased expression of genes involved in peroxisomal fatty acid oxidation (FAO) which compensated for the limited CPT-I-dependent FA transport into the mitochondria. In ischemia followed by reperfusion, the redirection of LCFA oxidation from mitochondria to peroxisomes protected the mitochondria from the accumulation of LCFA. In turn, the recovery of FAO resulted in significant reduction of myocardial infarct size. In conclusion, the decreased L-carnitine content in the heart preserves its peroxisomal and mitochondrial function after ischemia and improves cardiac recovery during reperfusion. The functional interplay between the decrease in L-carnitine and the PPARα/PGC1α pathway-induced redirection of FA metabolism protects the mitochondria against LCFA overload and provides a foundation for novel cardioprotective mechanisms.

Inhibition of L‐carnitine biosynthesis and transport by methyl‐γ‐butyrobetaine decreases fatty acid oxidation and protects against myocardial infarction

“…We then determined the effects of Methyl-GBB on the uptake and oxidation of LCFA in an isolated heart. In contrast to the previously observed effects of meldonium (Liepinsh et al, 2013b), the oxidation rate of labelled palmitate in the isolated heart was decreased by 40% ( Figure 4A). An increase in LCFA oxidation was observed after reperfusion in Methyl-GBB-treated group ( Figure 4A).…”

“…In previous studies, we have observed an increase in the nuclear content of PPAR‐α and PGC‐1α, as a response to decreased L‐carnitine content (Liepinsh et al ., 2011c; 2013b). The compensatory changes in the expression of the genes related to FAO and the redirection of LCFA flux from the mitochondria to the peroxisomes are clearly beneficial to preserve mitochondrial function and recovery after heart ischaemia (Liepinsh et al ., ). In this study, we observed that the decrease in L‐carnitine content did not induce substantial changes in gene expression involved in LCFA metabolism in normoxic hearts.…”

“…Determination of the acylcarnitines in the mitochondrial and heart tissue samples was performed by UPLC/MS/MS method . The sample preparation was performed as previously described (Blachnio-Zabielska et al, 2011) with modifications (Liepinsh et al, 2013b). The concentrations of acylcarnitines were measured using a 7-point standard curve of palmitoylcarnitine (10-1000 ng·mL −1 ).…”

“…Ischaemic heart disease (IHD) is a major medical problem causing disability and death for millions of people annually (Lavie et al, 2009). The important pathological consequences of IHD arise from the detrimental effects of the accumulation of long-chain fatty acids (LCFAs) in the case of acute ischaemia-reperfusion (Wang and Lopaschuk, 2007;Liepinsh et al, 2013b). Therefore, pharmacological intervention that targets LCFA accumulation has been suggested for the development of novel treatment strategies to improve the clinical outcomes of patients with IHD (Horowitz et al, 2010;Lopaschuk et al, 2010).…”

The Peroxisome-Mitochondria Connection: How and Why?

“…In the case where peroxisome biogenesis is completely blocked, such treatment also results in other mitochondrial perturbations, including structural alterations of the inner mitochondrial membrane [57,58,59], a reduction in the activities of multiple respiratory chain complexes [57,58,59], reduced mitochondrial DNA abundance [57], and an increase in mitochondrial volume [57,59]. On the other hand, an increase in catalase activity [109,114], peroxisomal β-oxidation [115] or peroxisome number [116] has been reported to ameliorate mitochondrial fitness and protect these organelles against oxidative insults. In reverse, to the best of our knowledge, there are no published studies that have addressed how specific defects in mitochondrial functions affect the redox state of peroxisomes, and this issue remains an unresolved open question.…”