The Mitochondrial Electron Transport Chain Regulates Expression and Secretion of the Lipoprotein APOE Open Access

Abstract

Mitochondria maintain cellular health through several cell-autonomous mechanisms, such as energy production and calcium buffering. While mitochondria are known for these cell-autonomous functions, they can also contribute to cellular homeostasis through non-cell autonomous mechanisms, including modulation of the secretion of proteins and metabolites. Regulation of protein secretion by mitochondria is established for relatively few proteins. These include inflammatory cytokines, growth factor mitokines, plasma protein alpha-fetoprotein, and a small number of mitochondrially-derived peptides. In this dissertation, I test the hypothesis that mitochondrial regulation of protein secretion is more extensive than previously appreciated. I focus on two inner mitochondrial membrane transporters, SLC25A1 and SLC25A4, linked to 22q11.2 deletion syndrome, a strong risk factor for several neurodevelopmental disorders. Genetic disruption of SLC25A1 or SLC25A4 leads to changes in the expression of secreted proteins on par in magnitude with changes in the expression of mitochondrial proteins, supporting the importance of mitochondria in secretome regulation. Loss of either SLC25A1 or SLC25A4 in cell lines caused robust upregulation of the expression and secretion of the lipoprotein APOE. Since APOE is the top genetic risk factor for late onset Alzheimer’s disease, I focused on APOE for further study. My work demonstrates that loss of SLC25A1 or SLC25A4 causes APOE upregulation through perturbed electron transport chain assembly. Moreover, direct genetic or pharmacological disruption of electron transport chain complexes I, III, and IV subunits and assembly factors also causes elevated APOE expression and secretion. This APOE upregulation phenotype extends to mitochondrial genes implicated as Alzheimer’s risk loci, which encode a complex I subunit and assembly factor. I show that mitochondrial regulation of APOE occurs in iPSC-derived astrocytes, in concert with changes in inflammatory gene expression, supporting the notion that mitochondria can initiate inflammatory signaling in the brain. Together, this body of work supports a new conception for Alzheimer’s pathogenesis, in which mitochondria can act upstream of APOE and modulate APOE-dependent disease processes. My findings also add to knowledge of how mitochondria regulate the secretome, providing the first evidence for mitochondria regulating the secretion of a lipoprotein.

Table of Contents

TABLE OF CONTENTS

 

 

PAGE

1.   CHAPTER 1: GENERAL INTRODUCTION

1

1.1 Conceptual background and the goals of this thesis

2

1.2 22q11.2 Deletion Syndrome

4

1.3 Disease mechanisms in 22q11 deletion syndrome

5

1.4 Mitochondria in models of 22q11 deletion syndrome

7

1.4.1 TXNRD2 and ROS regulation

7

1.4.2 MRPL40 and mitochondrial ribosomes

8

1.4.3 Disruption of the electron chain function and mitoribosomes mediated by SLC25A1

10

1.5 Parkinson’s disease and 22q11.2 microdeletion syndrome as conceptual guides to the neurobiology of APOE, an Alzheimer’s risk factor.

14

1.6 The neurobiology of APOE and Alzheimer’s disease

17

1.7 Significance of this dissertation research

20

2.   CHAPTER 2: APOE EXPRESSION AND SECRETION ARE MODULATED BY MITOCHONDRIAL DYSFUNCTION

24

2.1 Abstract

25

2.2 Introduction

26

2.3 Results

29

2.3.1 Genetic Disruption of Inner Mitochondrial Membrane Transporters Alters the Secretome

29

2.3.2 APOE Expression is Uncoupled from Changes in Cholesterol Synthesis Pathways

33

2.3.3 Perturbation of the Electron Transport Chain Complexes I and III Increases APOE Expression

38

2.3.4 Direct and Indirect Mechanisms Affecting Complex IV Biogenesis Increases APOE Expression

47

2.3.5 Mitochondrial Dysfunction Induces APOE Expression and Inflammatory Responses in Immortalized Cells and Human Astrocytes

57

2.3.6 The expression of APOE and respiratory chain subunits are inversely correlated in a mouse model of Alzheimer’s disease

61

2.3.7 SLC25A1-sensitive gene expression correlates with human cognitive trajectory during aging

63

2.4 Discussion

68

2.5 Materials and Methods

74

3.   CHAPTER 3: DISCUSSION

101

3.1 Summary of findings

102

3.2 Mechanisms of APOE upregulation

104

3.3 Mitochondria and Inflammation

107

3.4 Cellular functions of mitochondrial-mediated APOE upregulation           

110

3.5 Roles of APOE and mitochondria in Alzheimer’s disease

112

3.6 Influence of mitochondria on disease-associated regional and cell type vulnerabilities

114

3.7 Future directions for this research

116

3.8 Conclusions

118

4.   REFERENCES

120

About this Dissertation

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• Permission granted by the author to include this thesis or dissertation in this repository. All rights reserved by the author. Please contact the author for information regarding the reproduction and use of this thesis or dissertation.

School	Laney Graduate School
Department	Biological and Biomedical Sciences
Subfield / Discipline	Neuroscience
Degree	Ph.D.
Submission	Dissertation
Language	English
Research Field	Biology, Neuroscience Biology, Cell
Keyword	alzheimer's disease lipoproteins mitochondria microdeletion syndrome
Committee Chair / Thesis Advisor	Victor Faundez, Emory University
Committee Members	Yoland Smith, Emory University Jennifer Kwong, Emory University Steven Sloan, Emory University Shannon Gourley, Emory University

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