Mitochondrial protein phosphorylation: instigator or target of lipotoxicity?

Abstract

Lipotoxicity occurs as a consequence of chronic exposure of non-adipose tissue and cells to elevated concentrations of fatty acids, triglycerides and/or cholesterol. The contribution of mitochondria to lipotoxic cell dysfunction, damage and death is associated with elevated production of reactive oxygen species and initiation of apoptosis. Although there is a broad consensus on the involvement of these phenomena with lipotoxicity, the molecular mechanisms that initiate, mediate and trigger mitochondrial dysfunction in response to substrate overload remain unclear. Here, we focus on protein phosphorylation as an important phenomenon in lipotoxicity that harms mitochondria-related signal transduction and integration in cellular metabolism. Moreover, the degradation of mitochondria by mitophagy is discussed as an important landmark that leads to cellular apoptosis in lipotoxicity. Mitochondrial relay functionThe term 'lipotoxicity' describes the dysfunction of non-adipose tissue and cells that face chronic exposure to elevated fatty acids, triglycerides and/or cholesterol [1][2][3]. When plasma levels of prandial and postprandial fatty acids, triglycerides or cholesterol exceed the uptake capacity of adipose tissue, non-adipose tissue becomes overloaded with lipids, resulting in several metabolic imbalances and/or diseases. Once the oxidative capacity of these cells is exhausted, lipotoxic pathways are initiated that yield cellular dysfunction and, at worst, result in cell death. Although multiple lipotoxic events have been described [1][2][3] (e.g. induction of endoplasmic reticulum stress [4,5] by disruption of its structural integrity [6]) recent findings point to mitochondrial dysfunction as a key phenomenon in lipotoxicity leading to ominous signals [7][8][9][10][11].The mitochondria not only serve as the power plant of the cell but also act as a cellular relay, sensing multiple cellular and environmental parameters, including energy status, oxygen availability and activation patterns of cellular signal-transduction pathways. Mitochondria then integrate these inputs, adapting their activity and functions to, ultimately, tune cellular responsiveness with respect to the current demand of the cell [12] (Figure 1). In spite of the important tasks of the mitochondrion and in contrast to its functions in energy metabolism, its contribution to signal transduction has not been thoroughly investigated, and the [24,25]. Because similar pathways were also described as leading to cellular differentiation [17], the actual physiological outcome might depend on the pattern of activated pathways rather than on a single phenomenon. Thus, it is feasible that changes in the mitochondrial phosphoproteome caused by alterations in kinase activities are fundamental for the decisive setting of signaling patterns for cell survival or the initiation of cellular dysfunction in lipotoxicity leading to cell death. Three different scenarios affecting mitochondrial protein phosphorylation can be postulated in lipotoxicity ( Figure ...

Metabolic control of oocyte development: linking maternal nutrition and reproductive outcomes

“…Associated with elevated levels of follicular free fatty acid, obvious lipid accumulation was detected in oocytes from HFD mice [188]. When exposed to a high-lipid environment, cells accumulate triglyceride droplets and free fatty acids, causing significant damages to other cellular organelles, such as mitochondria and endoplasmic reticulum (ER); this process is termed lipotoxicity [206]. Mitochondrial dysfunction and ER stress in oocytes from obese and insulin-resistant mice have been reported by different groups [153, 170, 180, 188, 189, 200].…”

Age-Induced Changes in White, Brite, and Brown Adipose Depots: A Mini-Review

“…One hypothesis for the alteration in mitochondrial function is lipotoxicity, which has mostly been discussed in the context of muscle and liver and which can occur during adipose tissue hypertrophy, usually coupled to adipose tissue insulin resistance, when storage capacity of the adipocyte is exceeded. In this context, it was reported that the mitochondrial phosphoproteome is substantially altered, in response to a lipid overload; however, it remains unclear whether altered mitochondrial function is the driver of lipotoxicity or vice versa [59]. Several interventions have been described, which can reverse the phenotype of reduced mitochondrial function in WAT in obesity, the two most prominent examples being caloric restriction and treatment using PPARγ agonists [60].…”

Mitochondria in the pathogenesis of diabetes: a proteomic view

“…Comparative mitochondrial proteomics in different tissues of diabetic animal models have gained insights into the pathogenesis of diabetes and its complications, thus could provide more information for the development of drugs for the treatment of diabetes. Though great progress has been made in mitochondrial proteomics in diabetes, most of these studies solely focused on protein expression, however, mitochondrial protein post-translational modifications, such as phosphorylation, also played crucial roles in mitochondrial functioning (Thomson, 2002;Pagliarini and Dixon, 2006) and mitochondrial perturbations (Graier et al, 2009). Further studies to examine the changes in mitochondrial protein post-translational modifications with proteomic tools in diabetes affected animal model tissues, could provide more information and increase our understanding of the pathogenesis of diabetes.…”