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PI3K/AKT SIGNALING AND THE REGULATION OF THE MITOCHONDRIAL ENERGY-REDOX AXIS
by
Chen Li
A Dissertation Presented to the
FACULTY OF THE USC GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF PHILOSOPHY
(MOLECULAR PHARMACOLOGY AND TOXICOLOGY)
May 2012
Copyright 2012 Chen Li
Object Description
| Title | PI3K/AKT signaling and the regulation of the mitochondrial energy-redox axis |
| Author | Li, Chen |
| Author email | cli2@usc.edu;chenli1062011@gmail.com |
| Degree | Doctor of Philosophy |
| Document type | Dissertation |
| Degree program | Molecular Pharmacology and Toxicology |
| School | School of Pharmacy |
| Date defended/completed | 2012-03-26 |
| Date submitted | 2012-05-02 |
| Date approved | 2012-05-02 |
| Restricted until | 2012-05-02 |
| Date published | 2012-05-02 |
| Advisor (committee chair) | Cadenas, Enrique |
| Advisor (committee member) |
Stiles, Bangyan L. Kaplowitz, Neil |
| Abstract | The concept of the mitochondrial energy-redox axis integrates the mitochondrial energy-transduction and redox status as a concerted process with the two components inter-linked by the reducing equivalents (i.e., NAD(P)⁺/NAD(P)H). Decrease of mitochondrial energy transduction and pro-oxidant shift of cellular redox status precede the pathological changes of several diseases (i.e., diabetes) and are key features of aging. Mitochondria are also recipients of cellular signaling regulations such as MAPKs and PI3K/AKT pathway of insulin signaling. These studies are aimed at assessing the effect of the PI3K/AKT signaling pathway in the mitochondrial energy-redox axis and depicting the molecular mechanisms inherent in the effect. A liver-specific Pten deletion model that shows a robust insulin signaling was used to study how the PI3K/AKT pathways affect the mitochondrial energy-redox axis. The hypothesis to be tested is that liver-specific Pten deletion up-regulates mitochondrial bioenergetics through modulation of PI3K/AKT signaling pathways, which further affect mitochondrial and cellular H₂O₂ homeostasis, redox status, and the intrinsic apoptotic pathway. ❧ These studies revealed that mitochondrial bioenergetics is regulated by PI3K/AKT signaling through three mechanisms: 1) AKT increases glycolysis and thus, a higher substrate (pyruvate) supply to mitochondria; 2) AKT, upon activation, translocates to mitochondria and phosphorylates ATP synthase subunits α/β leading to a higher ATP synthase activity; 3) AKT phosphorylates / inactivates GSK3β, which is correlated with the decrease of the phosphorylation (inactivation) of mitochondria PDH-E1α at Ser²⁷³. ❧ These effects translate in a higher bioenergetic capacity of mitochondria and, consequently, a lower generation of H2O2 by these organelles. This is attributed to: 1) the highly oxidized state of the mitochondrial respiratory complexes; 2) the higher expression of mitochondrial and cellular H₂O₂ removal enzymes; 3) through modulation of the expression of mitochondrial isocitrate dehydrogenase-2 and consequently the increased generation of reducing equivalents (NADPH), which are critical for the mitochondrial H₂O₂ removal system. The study of AKT activation on mitochondria as a function of age shows that mitochondria of Pten⁻/⁻ liver have a significantly reduced H₂O₂ generation level than control at older age (9-12 month old) and AKT activation antagonizes the increase of mitochondrial source of H₂O₂ production caused by aging. |
| Keyword | mitochondrial respiration; PI3K; AKT; PTEN; GSK3β; pyruvate dehydrogenase; ATP synthase; hepatocytes; bioenergetics; redox status; oxidative stress; aging |
| Language | English |
| Part of collection | University of Southern California dissertations and theses |
| Publisher (of the original version) | University of Southern California |
| Place of publication (of the original version) | Los Angeles, California |
| Publisher (of the digital version) | University of Southern California. Libraries |
| Provenance | Electronically uploaded by the author |
| Type | texts |
| Legacy record ID | usctheses-m |
| Contributing entity | University of Southern California |
| Rights | Li, Chen |
| Physical access | The author retains rights to his/her dissertation, thesis or other graduate work according to U.S. copyright law. Electronic access is being provided by the USC Libraries in agreement with the author, as the original true and official version of the work, but does not grant the reader permission to use the work if the desired use is covered by copyright. It is the author, as rights holder, who must provide use permission if such use is covered by copyright. The original signature page accompanying the original submission of the work to the USC Libraries is retained by the USC Libraries and a copy of it may be obtained by authorized requesters contacting the repository e-mail address given. |
| Repository name | University of Southern California Digital Library |
| Repository address | USC Digital Library, University of Southern California, University Park Campus MC 7002, 106 University Village, Los Angeles, California 90089-7002, USA |
| Repository email | cisadmin@dots.usc.edu |
| Archival file | uscthesesreloadpub_Volume4/etd-LiChen-718.pdf |
Description
| Title | Page 1 |
| Contributing entity | University of Southern California |
| Repository email | cisadmin@dots.usc.edu |
| Full text | PI3K/AKT SIGNALING AND THE REGULATION OF THE MITOCHONDRIAL ENERGY-REDOX AXIS by Chen Li A Dissertation Presented to the FACULTY OF THE USC GRADUATE SCHOOL UNIVERSITY OF SOUTHERN CALIFORNIA In Partial Fulfillment of the Requirements for the Degree DOCTOR OF PHILOSOPHY (MOLECULAR PHARMACOLOGY AND TOXICOLOGY) May 2012 Copyright 2012 Chen Li |
