Phospholipids are the basic structure block of eukaryotic membranes, in both the outer and inner membranes, which delimit cell organelles. Phospholipids can also be damaged by oxidative stress produced by mitochondria, for instance, becoming oxidized phospholipids. These damaged phospholipids have been related to prevalent diseases such as atherosclerosis or non-alcoholic steatohepatitis (NASH) because they alter gene expression and induce cellular stress and apoptosis. One of the main sites of phospholipid synthesis is the endoplasmic reticulum (ER). ER association with other organelles through membrane contact sites (MCS) provides a close apposition for lipid transport. Additionally, an important advance in this small cytosolic gap are lipid transfer proteins (LTPs), which accelerate and modulate the distribution of phospholipids in other organelles. In this regard, LTPs can be established as an essential point within phospholipid circulation, as relevant data show impaired phospholipid transport when LTPs are defected. This review will focus on phospholipid function, metabolism, non-vesicular transport, and associated diseases.

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Lipid Droplets (LD) are highly dynamic storage organelles. In the liver, its accumulation causes non-alcoholic fatty liver (NAFL) that can progress to a more severe disease stage, nonalcoholic steatohepatitis (NASH). In hepatic and non-hepatic tissues LD interacts with mitochondria impacting lipid homeostasis. However, whether exercise modulates this interaction in the liver has not been studied yet. Our objective is to determine whether exercise modifies LD-mitochondria interaction in hepatocytes and if this interaction has an association with the severity of the disease. Two different models of NAFLD, a high fat diet (HFD) to evaluate NAFL and a methionine choline deficient diet (MCD) to evaluate NASH, were used to analyze the effects of aerobic exercise in the liver. Our results in the NAFL model showed that exercise decreased the severity of the disease and improved physical capacity compared to sedentary HFD mice. In this regard, although exercise increased the number of LD in hepatocytes, LD were smaller in size than in the sedentary HFD mice. Notably, while sedentary HFD mice increased hepatic lipid droplet (LD)-mitochondria interaction, in exercised animals, this interaction was decreased. Additionally, exercise decreased the size of the LD bound to mitochondria, and this peridroplet mitochondria (PDM) exhibited higher basal respiration and ATP synthesis capacity than PDM from sedentary HFD mice. Besides, we found a positive correlation that predicts the severity of NAFL between LD-mitochondria interaction in the liver and plasmatic ALT transaminases. This correlation is also positive between hepatic LD-mitochondria interaction and the area under the glucose tolerance test curve in this model. Our results in the NASH model resemble, to a greater extent, what we observed in the NAFL model. In NASH, exercise also reduced collagen accumulation, decreased LD-mitochondria interaction, and reduced the size of LD coupled to mitochondria compared to sedentary MCD mice. In all, our results show that aerobic exercise decreases LD-mitochondria interaction in hepatocytes and this interaction is associated with less severity of NAFL and NASH. We propose that exercise provokes an improvement of NAFLD by reduction of the hepatic LD-mitochondria interaction that in turn increase peridroplet mitochondria activity.

Type 2 diabetes mellitus (T2D) affects millions of people worldwide and is one of the leading causes of morbidity and mortality. The skeletal muscle (SKM) is the most important tissue involved in maintaining glucose homeostasis and substrate oxidation, and it undergoes insulin resistance in T2D. In this study, we identify the existence of alterations in the expression of mitochondrial aminoacyl-tRNA synthetases (mt-aaRSs) in skeletal muscle from two different forms of T2D: early-onset type 2 diabetes (YT2) (onset of the disease before 30 years of age) and the classical form of the disease (OT2). GSEA analysis from microarray studies revealed the repression of mitochondrial mt-aaRSs independently of age, which was validated by real-time PCR assays. In agreement with this, a reduced expression of several encoding mt-aaRSs was also detected in skeletal muscle from diabetic (db/db) mice but not in obese ob/ob mice. In addition, the expression of the mt-aaRSs proteins most relevant in the synthesis of mitochondrial proteins, threonyl-tRNA, and leucyl-tRNA synthetases (LARS2 and TARS2) were also repressed in muscle from db/db mice. It is likely that these alterations participate in the reduced expression of proteins synthesized in the mitochondria detected in db/db mice. Because it is known that, nitrosative stress inhibits aminoacylation of TARS2 and LARS2 activities, we noticed an increased protein expression of iNOS in isolated muscle mitochondria in diabetic mice. Our results indicate a reduced expression of mitochondrial mt-aaRSs in skeletal muscle from T2D patients, which may participate in the reduced expression of proteins synthesized in mitochondria. This may be due to an enhanced NO production secondary to enhanced iNOS expression in muscle under diabetic conditions.

Endoplasmic Reticulum (ER) is the largest and one of the most complex cellular structures, indicating its widespread importance and variety of functions, including synthesis of membrane and secreted proteins, protein folding, calcium storage, and membrane lipid biogenesis. Moreover, the ER is implicated in cholesterol, plasmalogen, phospholipid, and sphingomyelin biosynthesis. Furthermore, the ER is in contact with most cellular organelles, such as mitochondria, peroxisomes, Golgi apparatus, lipid droplets, plasma membrane, etc. Peroxisomes are synthesized from a specific ER section, and they are related to very-long-chain fatty acid metabolism. Similarly, lipid droplets are vital structures in lipid homeostasis that are formed from the ER membrane. Additionally, there is a specific region between the ER-mitochondria interface called Mitochondria-Associated Membranes (MAMs). This small cytosolic gap plays a key role in several crucial mechanisms from autophagosome synthesis to phospholipid transfer. Due to the importance of the ER in a variety of biological processes, alterations in its functionality have relevant implications for multiple diseases. Nowadays, a plethora of pathologies like non-alcoholic steatohepatitis (NASH), cancer, and neurological alterations have been associated with ER malfunctions.