| Mitochondrial diseases are multisystem genetic disorders with a heterogenous set of symptoms. Since the first initial case report, more than 150 distinct genetic mitochondrial syndromes have been defined. Most of these syndromes are multisystemic, including mitochondrial encephalomyopathy with lactic acidosis and stroke-like episode (MELAS), myoclonic epilepsy with ragged-red fibers (MERRF), Leigh syndrome (LS), etc. Some are tissue specific, e.g. sensorineural deafness, Leber’s hereditary optic neuropathy (LHON). The G11778A mutation is typically associated with the LHON phenotype, and is by far the most common LHON mutation.Leigh syndrome (OMIM number:256000) is a subacute necrotizing encephalopathy characterized by almost identical brain changes but considerable clinical and genetic heterogeneity. Clinical hallmarks include regression or psychomotor delay, weakness, hypotonia, ataxia, intention tremor associated with lactic acidosis in the blood, cerebrospinal fluid, or urine. The prognosis is poor and most patients die before the age of 5 years. Leigh syndrome can be caused by mutations affecting the function of respiratory chain (I, II, IV, or V), coenzyme Q, or the pyruvate dehydrogenase complexAutosomal dominant progressive external ophthalmoplegia (adPEO, OMIM number:609286) is a common adult onset mitochondrial disease, with typical features of ptosis, external ophthalmoplegia, slowly progressive weakness of skeletal muscle. Some patients may also have ataxia, neuropathy, hearing loss, etc. To date, adPEO has been associated with mutations in five nDNA genes [1,2:ANT1, encoding adenine nucleotide translocator 1; C10orf2 (also known as Twinkle) encoding a putative mtDNA helicase; POLG, encoding the catalytic subunit of polymerase y; POLG2, encoding the accessory subunit of POLG; and OPA1, encoding a dynamin-related GTPase. The number of report on pathogenic Twinkle mutations is limited and a systematic literature review is lacking. More recently the physiological function of Twinkle protein has been described in detail, which enables us to better understanding the phenotypic consequence of the mutations in Twinkle gene..Since its discovery in 2005, fibroblast growth factor (FGF21) has attracted high interest due to its wide range of beneficial effect in metabolic homeostasis. These effects include regulating glucose and lipid metabolism, and enhancing insulin sensitivity [3], mitochondrial oxidative function and thermogenesis. Unlike most of the members from FGFs family, which require a heparin domain for efficient binding to the FGF receptors (FGFRs), FGF21, as a member of the endocrine FGF19 family, is secreted into the circulation, and can travel to sites distal from its origin and acts predominantly via endocrine mechanism.Human FGF21 is a 187 amino acid protein which is predominantly secreted by liver and other tissues involved in glucose and lipid metabolism such as adipose, pancrease and muscle. Studies in mouse indicate that the major site for FGF21 production is liver. Nevertheless, both the liver and serum levels of FGF21 are low under normal physiological condition. However, both hepatic and serum levels of FGF21 are dramatically elevated during fasting and ketogenic diet, and rapidly suppressed by refeeding. Apart from the liver, the adipocytes also express and secrete FGF21 at time of thermogenic activation. However, the major source of the serum levels of FGF21 under normal physiological condition has yet to be discovered and some debate exists as to the relevance of basal serum levels of FGF21 to its regulation ofphysiology.Apart from starvation and obesity, there are studies on animals and human indicating that FGF21 is induced in individual tissues in response to specific diseases such as type 2 diabetes, coronary heart disease, liver injury, chemical insult and hepatic regenerative response. Interestingly, several recent studies demonstrate that FGF21 is upregulated in patients with mitochondrial disorders, mice with mitochondrial respiratory chain deficiency and mice defective in muscular autophagy/mitophagy. Despite the importance of FGF21 as a sensitive biomarker of muscle-manifesting mitochondrial disease, little is known about the role of FGF21 in skeletal muscle tissue. Additionally, the mechanisms by which FGF21 regulates mitochondrial oxidative function remain unclear.The mammalian target of rapamycin (mTOR) signaling pathway is a master regulator of cell metabolism and energy homeostasis[14]. The mTOR protein is a 289-kDa serine-threonine kinase and nucleates two distinct multi-protein complex, mTOR complex I (mTORC1) and mTOR complex Ⅱ (mTORC2). Several signals has been demonstrated to activate mTORC1, such as Ras signaling, PI3K-AKT pathway and Wnt signaling[15]. Recently, mTORC1 has been to shown to play an important role in mitochondrial metabolism and biogenesis.Here we demonstrate that FGF21 is induced in skeletal muscle tissue of patients with mitochondrial oxidative phosphorylation deficiency and compensates for energy metabolism deficiency by modulating mTOR activities via PI3K-AKT pathway in skeletal muscle cell. FGF21 increases the expression levels of Yin Yang 1 (YY1) and Peroxisome proliferator-activated receptor gamma, coactivator 1 alpha (PGC-1α). The activation of these key metabolic regulators result in enhancing mitochondrial oxidative function, accounting for the compensatory beneficial effect of FGF21 in mitochondrial diseasePART ONESkeletal muscle increase FGF21 expression in mitochondrial disorder to compensate for the energy metabolic insufficiency by activating mTOR-YYl-PGCla pathwayFibroblast growth factor 21 (FGF21) is a growth factor with pleiotropic effects on regulating lipid and glucose metabolism. Its expression is increased in skeletal muscle of mice and human with mitochondrial disorder. However, the effects of FGF21 on skeletal muscle in response to mitochondrial respiratory chain deficiency is largely unknown. Here we demonstrated that the increased expression of FGF21 is a compensatory response to respiratory chain deficiency. The mRNA and protein levels of FGF21 were robustly raised in skeletal muscle from patient with mitochondrial myopathy or MELAS. The mammalian target of rapamycin (mTOR) phosphorylation levels and its downstream targets, Yin Yang 1 (YY1) and Peroxisome proliferator-activated receptor gamma, coactivator 1 alpha (PGC-1α) were increased by FGF21 treatment in C2C12 myoblasts. Activation of mTOR-YY1-PGCla pathway by FGF21 in myoblasts regulated energy homeostasis as demonstrated by significant increases in intracellular ATP synthesis, the oxygen consumption rate, the activity of citrate synthase, glycolysis, mitochondrial DNA copy number and induction the expression of key energy metabolic genes.The effects of FGF21 on mitochondrial function required phosphoinositide 3-kinase (PI3K), which activate mTOR. Inhibition of PI3K, mTOR, YY1 and PGC-1α activities attenuated the stimulating effects of FGF21 on intracellular ATP levels and mitochondrial genes expression. Our finding revealed that mitochondrial respiratory chain deficiency elicited a compensatory response in skeletal muscle by increased FGF21 expression levels in muscle, which resulting in enhanced mitochondrial function through an mTOR-YY1-PGC1α dependent pathway in skeletal muscle.PART TWONovel mitochondrial C15620A variant may modulate the phenotype of mitochondrial G11778A mutation in a Chinese family with Leigh syndromeWe report a case of 3 years old boy who presented with Leigh syndrome but carried a mitochondrial G11778A mutation in the fourth subunit of the NADH dehydrogenase gene (MTND4). Additional to G11778A mutation, a novel C15620A variant was detected, which resulted in the conversion of leucine to isoleucine in the mitochondrial cytochrome b (MTCYB) gene. As G11778A mutation is the most common mutation associated with Leber’s hereditary optic neuropathy (LHON), given the unusual phenotype, the C15620A mutation was postulated to influence the pathogenicity of the G11778A mutation. This case further expands the clinical spectrum associated with the primary G11778A LHON mutation.PART THREETwinkle mutations in two Chinese families with autosomal dominant progressive external ophthalmoplegiaAutosomal dominant progressive external ophthalmoplegia (adPEO) is a common adult onset mitochondrial disease caused by mutations in nuclear DNA (nDNA). Twinkle is one of the nuclear genes associated with adPEO. Clinical, histochemical, and molecular genetics findings of 6 patients from two Chinese families with adPEO were reported. Two point mutations (c.1423G>C, p.A475P and c.1061G>C, p.R354P) of Twinkle gene have been found. Multiple mtDNA deletions were also detected in patient’s muscle and fibroblasts.This study confirms two mutations in Chinese adPEO families, which are firstly reported in the Chinese population. |
