Mitochondrial protein dysfunction in pathogenesis of neurological diseases

Abstract

Mitochondria are essential organelles for neuronal function and cell survival. Besides the well-known bioenergetics, additional mitochondrial roles in calcium signaling, lipid biogenesis, regulation of reactive oxygen species, and apoptosis are pivotal in diverse cellular processes. The mitochondrial proteome encompasses about 1,500 proteins encoded by both the nuclear DNA and the maternally inherited mitochondrial DNA. Mutations in the nuclear or mitochondrial genome, or combinations of both, can result in mitochondrial protein deficiencies and mitochondrial malfunction. Therefore, mitochondrial quality control by proteins involved in various surveillance mechanisms is critical for neuronal integrity and viability. Abnormal proteins involved in mitochondrial bioenergetics, dynamics, mitophagy, import machinery, ion channels, and mitochondrial DNA maintenance have been linked to the pathogenesis of a number of neurological diseases. The goal of this review is to give an overview of these pathways and to summarize the interconnections between mitochondrial protein dysfunction and neurological diseases.

Keywords: mitochondrial bioenergetics; mitochondrial dynamics; mitochondrial import machinery; mitochondrial proteins; mitophagy; mtDNA maintenance; neurological diseases; pathogenesis.

Figure 1

The main pathways leading to mitochondrial-associated neurological disorders. Genetic or environmental factors can cause mutations of mitochondrial proteins, which lead to mitochondrial malfunction. Neurological disorders may result from damaged mitochondrial bioenergetics, imbalanced mitochondrial dynamics, defective mitophagy, impaired maintenance of mitochondrial genome, compromised mitochondrial importing machinery, altered mitochondrial ion channels, or combinations thereof.

Figure 2

Schematic depiction of the mitochondrial electron transport chain. The electron transport chain (ETC) consists of complexes I to IV as well as two free electron carriers, CoQ and Cyt c. Reducing equivalents (NADH, FADH2) provide electrons flowing through complexes I, the ubiquinone cycle (Q/QH2), III, IV, and to the final acceptor O₂. The electron flows through complexes resulting in the pumping of protons to the IMS, which creates a membrane potential used by the F₁F_o-ATP synthase to drive the production of ATP.

Figure 3

Schematic depiction of mitochondrial fusion and fission in neurons. Mitochondrial fusion relies on membrane proteins Mfn1/2 and OPA1 residing in the OMM and the IMM, respectively. Mfn1 and Mfn2 form homo-oligomeric (Mfn1-Mfn1 or Mfn2-Mfn2) and hetero-oligomeric (Mfn1-Mfn2) complexes in trans between the opposing mitochondria to induce the OMM fusion. The long and short forms of OPA1 synergistically catalyze the tethering and fusion of the IMM. Mitochondrial fission begins with the ER contacts with the OMM at the ER-mitochondria contact sites, and ER wraps tightly around the mitochondria to form constrictions. The cytosolic Drp1 is subsequently recruited to the OMM via multiple membrane adaptors MiD51, MiD49, Fis1, and Mff. Drp1 oligomerizes at the ER-marked pre-constriction sites, forming a ring-like structure around the mitochondria for further membrane constriction.

Figure 4

Schematic overview of PINK1/Parkin mediated mitophagy. PINK1 accumulates at the surface of damaged mitochondria when the constitutive degradation of PINK in the mitochondrial matrix is inhibited. Subsequent homodimerization of PINK1 on the OMM leads to autophosphorylation, which promotes its activation. Activated PINK1 phosphorylates ubiquitin to recruit parkin, an E3 ubiquitin ligase, to the mitochondrial membrane. PINK1 regulates the localization and activity of parkin through phosphorylation of both ubiquitin and the ubiquitin-like domain of parkin. This process leads to ubiquitination of mitochondrial proteins on the OMM that can then be bound by autophagic proteins, ultimately triggering the formation of autophagosomes that deliver the damaged mitochondria to lysosomes for degradation.

Figure 5

Schematic diagram of critical proteins required for the replication and transcription of mtDNA. TWINKLE is an mtDNA helicase that catalyzes the unwinding of duplex DNA using energy from NTP hydrolysis. Mitochondrial single stranded DNA-binding protein (mtSSB) exists as a stable tetramer and binds single-stranded DNA intermediates that form transiently during genome maintenance. DNA polymerase gamma (POLγ) is a DNA polymerase that synthesizes a nascent strand using one of the unwound parental template strands at the replication fork. Mitochondrial transcription factor A (TFAM) is a master regulator of mitochondrial transcription initiation and mtDNA replication that binds the promoter region of mtDNA in a sequence-specific manner and thereby initiates promoter-specific transcription or replication from the light-strand promoter. Mitochondrial RNA polymerase (POLRMT) is an RNA polymerase that executes the transcription of the mtDNA.

Figure 6

Overview of the major mitochondrial protein import pathways. Mitochondrial precursor proteins are synthesized in the cytosol, transported to the mitochondria, and directed to the correct mitochondrial compartments. Five major protein import pathways have been identified so far: (1) Presequence-carrying preproteins are imported through the translocase of the outer mitochondrial membrane (TOM) and the translocase of the inner mitochondrial membrane (TIM23) complexes. Proteins containing a hydrophobic sorting signal are released into the inner mitochondrial membrane (IMM), while hydrophilic proteins are imported into the matrix with the help of the presequence translocase-associated motor (PAM) complex. Membrane potential across the IMM is essential for the entry of presequences into the matrix. The presequences are cleaved by the mitochondrial processing peptidase (MPP) and additional proteolytic processing occurs by intermediate cleaving peptidases. Presequence-carrying precursors that are integrated into the IMM are either directly released from the TIM23 complex or transported into the matrix, followed by further insertion into the IMM with the help of Oxa1; (2) Cysteine-rich proteins of the intermembrane space (IMS) are imported by TOM and the mitochondrial IMS import and assembly (MIA) system, which inserts disulfide bonds in the imported proteins; (3) The precursors of β-barrel proteins are translocated through the TOM complex to the TIM9/10 in the IMS and are inserted into the outer mitochondrial membrane (OMM) by the sorting and assembly machinery (SAM); (4) The precursors of metabolite carriers of the IMM are imported via the TOM complex, small TIM9/10 chaperones, and the carrier translocase TIM22 complex; and (5) Some proteins with α-helical transmembrane segments are inserted into the OMM by the mitochondrial import (MIM) complex.

Figure 7

Schematic overview of mitochondrial ion channels that are implicated in neurodegeneration. Mitochondrial ion channels are a group of integral membrane proteins mediating ionic fluxes across the mitochondrial membranes. VDAC is a voltage-dependent anion channel residing in the OMM and MCU is a mitochondrial calcium uniporter in the IMM. PTP is a mitochondrial permeability transition pore that allows mitochondria to undergo a sudden increase of permeability, including VDAC in the OMM and the adenine nucleotide translocase (ANT) in the IMM. Cyclophilin D (CypD) in the matrix is a sensitizer of PTP. Peripheral benzodiazepine receptor (BPR), hexokinase (HK), and creatine kinase (CK) are the other components of PTP.