東大西原博士の糖尿病の重症化は内呼吸障害すなわちミトコンドリアの変調という説は興味深い。食やストレスだけではなくて遺伝や年によるものもあると思われるが、ミトコンドリアがつぶれることで分裂病、うつ病、自閉症につながるのは怖いことである。
人間の一呼吸の中に外呼吸（肺）と肝臓からの栄養血流が合体し、さらに血流で６０兆個の細胞に運ばれているのである。１秒に１個の細胞に探訪しても一生かかっても不可能であるが、生体内では常時行なわれている。しかも一つ一つの細胞は動的である再構成で二度と同じものであることはない。
各細胞に運ばれた酸素分子はミトコンドリアの内呼吸に使われ、エネルギー生産とエネルギー消化が行なわれる。前段の解糖系ではグルコースのCH,CC結合のエネルギーが巧妙に取り出されて最終的にはプロトンH+と電子となりミトコンドリアへ行きH2Oとなる。
こんな複雑なことが一呼吸で行なわれているのであるが、これを意識している人は居るまい。瞑想実践者とて知らないことである。
西原氏の内呼吸障害は解糖系に正しく対処してきたミトコンドリアがつぶれたという考え方が面白いしガンなどの発生とも関連してくる。
現代内科医学は対処療法ばかりで生の根本を見ようとはしない。
cell.com/trends/endocrinology-metabolism/fulltext/S1043-2760(12)00096-3
▼Mitochondria and energy homeostasis
The essential roles of mitochondria in numerous aspects of metabolic regulation position them at center stage in the control of global energy homeostasis.
Mitochondrial metabolism is both the origin and target of multiple nutrient signals that orchestrate integrated physiological responses to maintain cellular insulin sensitivity.
In particular, glucose and lipid metabolismlargely depend on mitochondria to metabolize these nutrients and generate cellular energy in the form of ATP [1xObesity and the regulation of energy balance. Spiegelman, B.M. and Flier, J.S. Cell. 2001; 104: 531–543
All cells are affected by mitochondrial dysfunction機能障害. However, the primary tissues most negatively influenced by suboptimal mitochondrial performance are those that rely most heavily on mitochondrial function, such as skeletal and cardiac muscle, liver, and adipose tissue.
Metabolic imbalance of nutrient signal input, energy production, and/or oxidative respiration results in ‘mitochondrial dysfunction’. Although we appreciate the association between changes in mitochondrial function and the pathogenesis of obesity-driven insulin resistance [2xThe role of mitochondria in the pathogenesis of type 2 diabetes. Patti, M.E. and Corvera, S. Endocr. Rev. 2010; 31: 364–395
it is still widely debated whether such changes are a cause or a consequence of insulin resistance. In particular, energy-sensing cellular rheostats detect explicit signals of mitochondrial activity, such as the NAD+:NADH ratio, the AMP:ATP ratio, or acetyl-CoA levels; such signals become dysregulated with the onset of obesity and type 2 diabetes (T2DM).
Although a major role has been established for WAT in regulating energy intake, energy expenditure, and insulin resistance, the functional role of WAT mitochondria has received less attention. Over the past decade, several studies have highlighted the potential relevance of mitochondria in the cellular physiology of the adipocyte in WAT and its impact on systemic metabolic regulation. Here, we would like to
(i) highlight the impact that mitochondrial activity has on WAT （white adipose tissue） function , focusing explicitly on the white adipocyte;
(ii) discuss the means by which mitochondria in adipocytes 脂肪細胞 become compromised – and how such perturbations alter whole-body homeostasis;
(iii) elaborate on how the intracellular dynamics and key pathways within the adipocyte acclimatize to mitochondrial dysfunction; and
(iv) highlight promising therapeutic avenues that aim to improve adipocyte mitochondrial function.
▼Adequate mitochondrial function is essential for white adipocyte biology
WAT is now established as a major endocrine organ that impacts directly or indirectly on the physiological functions of almost all cell types.
Representing around 10% of total bodyweight in lean adults, WAT can achieve >50% in obese subjects [4xThe secretory function of adipocytes in the physiology of white adipose tissue. Wang, P. et al. J. Cell Physiol. 2008; 216: 3–13
. It is therefore not surprising that any obesity-induced changes in WAT mitochondria can substantially disrupt whole-body energy homeostasis.
The white adipocyte displays a unique structure, most frequently seen with a single large lipid droplet associated with relatively low cytoplasmic volume and reduced mitochondrial density.
medscape.com/viewarticle/739625_6
Schematic representation of the plasticity of white adipose tissue (WAT) and acquirement of a "brown-like" phenotype. White adipocytes contain a large unilocular triglyceride-rich lipid droplet (LD) with an offset nucleus (N) and a few mitochondria within the limited cytoplasm (Cyt) area. Chronic activation of adenosine monophosphate kinase (AMPK) up-regulates the expression and activity of peroxisome proliferator-activated receptor-γ (PPAR-γ) coactivator-1α (PGC-1α) and PPAR-γ. This cascade of events promotes mitochondrial biogenesis, which in the presence of increased PRDM16 expression induces adipocyte differentiation toward the phenotype of brown adipocytes. Typical brown adipocytes have multiple LD (multilocular) and a much larger cytoplasm space, which is populated densely with mitochondria, rendering brown adipose tissue highly oxidative. We hypothesize that through chronic AMPK activation, white adipocytes shift metabolism toward energy dissipation versus storage. This appears to occur through the acquisition of metabolic characteristics that are typical of brown adipocytes, which could be of great relevance for the treatment of obesity and its related metabolic disorders. Arrows (→) denote stimulation.
Despite containing relatively low mitochondrial mass compared to its overall size, the adipocyte interprets nutritional and hormonal cues in its microenvironment, then coordinates its mitochondrial response either to oxidize incoming FAs and carbohydrate fuels through the tricarboxylic acid (TCA) cycle and the respiratory chain, or to store these fuels safely in the form of triglycerides (TGs) until whole-body energy requirements signal for their release [5xAdipose tissue remodeling and obesity.
Mitochondria play an essential role in many different pathways in the adipocyte. The synchronized initiation of adipogenesis and mitochondrial biogenesis indicates that mitochondria play a pertinent role in the differentiation and maturation of adipocytes [6xMitochondrial (dys)function in adipocyte (de)differentiation and systemic metabolic alterations.
A recent study by Tormos and colleagues confirmed that the early events of enhanced mitochondrial metabolism, biogenesis and reactive oxygen species (ROS) production [specifically through complex III of the electron transport chain (ETC)], are crucial for the initiation and promotion of adipocyte differentiation in an mTORC1-dependent manner.
Consistent with this idea, antioxidant treatment blocks adipocyte differentiation whereas ROS, through exogenous hydrogen peroxide treatment of cells, can restore the differentiation process, as judged by increased adipocyte lipid accumulation and induction of adipogenic genes.
An intriguing suggestion is that ROS, primarily in the form of H2O2, are essential to initiate the PPARγ transcriptional machinery necessary to evoke adipocyte differentiation. Alternatively, ROS may play an important role in insulin signal transduction.
Although extremely high levels of ROS unquestionably cause cellular damage, ROS production in moderation may, however, serve to maintain cellular homeostasis by creating a tolerable oxidative environment that permits and sustains preadipocyte differentiation without inflicting cellular damage. Future studies examining the precise function of ROS in complementing the intricate process of adipocyte differentiation should prove illuminating, particularly in the context of a metabolically imbalanced environment.
In addition, in differentiating preadipocytes, mitochondria must generate and sustain sufficient ATP to support highly energy-consuming lipogenic processes, while still maintaining normal cellular activity9.
During nutrient uptake, mitochondria must provide acetyl-CoA derived from glucose metabolism as a substrate for FA synthesis. The conversion of the glucose metabolite pyruvate to acetyl-CoA takes place exclusively within the mitochondrial matrix. Furthermore, glycerol-3-phosphate, a precursor substrate for FA esterification, is produced by mitochondria and is required for the packaging of lipids in the form of TGs into the lipid droplet. In light of this, it has been proposed that ‘free fatty acid (FFA) recycling in the adipocyte’ (a TG-to-FA cycle) is a crucial sequence of events that determine systemic FFA concentrations .
Many of these processes are substrate-driven. Given that mitochondrial β-oxidation rates are interconnected with glyceroneogenic pathways and FA esterification processes , this highlights the potential of alleviating FA flux through the oxidative pathway by capturing and esterifying FAs into the local TG pool.
Mitochondria and energy homeostasis
Adequate mitochondrial function is essential for white adipocyte biologyMitochondrial dysfunction in adipocytes: contributors and consequences The onset of obesity and T2DM Lipid-induced ROS formationCompromised mitochondria alter the intracellular machinery of the adipocyte Preadipocyte differentiation and mitochondrial biogenesis Lipogenesis, lipolysis, and FA re-esterificationTherapeutic interventions that improve mitochondrial function Pharmacological interventions: thiazolidinediones (TZDs) Antioxidants and chemical uncouplers Exercise and caloric restrictionConcluding remarksReferences
▼Mitochondrial dysfunction in adipocytes: contributors and consequences
Compromised mitochondrial function may arise from acute cellular or systemic disruption. A more precise definition of mitochondrial dysfunction is provided in Box 1Box 1. Key contributors to mitochondrial dysfunction include excessive nutrient supply, which subsequently contributes to ROS formation and toxic lipid species production, genetic factors, endoplasmic reticulum (ER) stress (detailed in Box 2Box 2), aging and/or proinflammatory processes, and altered mitochondrial fission that severely disrupts the dynamic mitochondrial network fission process; all single-handedly or collectively contribute to insulin resistance.
The contributions of acyl-carnitine accumulation and ceramide production are described in Box 3Box 3.