Unlocking the Complexity of Mitochondrial DNA: A Key to Understanding Neurodegenerative Disease Caused by Injury

Abstract

Neurodegenerative disorders that are triggered by injury typically have variable and unpredictable outcomes due to the complex and multifactorial cascade of events following the injury and during recovery. Hence, several factors beyond the initial injury likely contribute to the disease progression and pathology, and among these are genetic factors. Genetics is a recognized factor in determining the outcome of common neurodegenerative diseases. The role of mitochondrial genetics and function in traditional neurodegenerative diseases, such as Alzheimer’s and Parkinson’s diseases, is well-established. Much less is known about mitochondrial genetics, however, regarding neurodegenerative diseases that result from injuries such as traumatic brain injury and ischaemic stroke. We discuss the potential role of mitochondrial DNA genetics in the progression and outcome of injury-related neurodegenerative diseases. We present a guide for understanding mitochondrial genetic variation, along with the nuances of quantifying mitochondrial DNA variation. Evidence supporting a role for mitochondrial DNA as a risk factor for neurodegenerative disease is also reviewed and examined. Further research into the impact of mitochondrial DNA on neurodegenerative disease resulting from injury will likely offer key insights into the genetic factors that determine the outcome of these diseases together with potential targets for treatment.

Cell energy metabolism and bone formation

“…IMM integrity is crucial for mitochondrial OxPhos and other activities ( Brand and Nicholls, 2011 ); 2) Mitochondria can fuse and fission depending on cell requirements and can exchange mtDNA, proteins, and metabolites during fusion. Fission is required for normal cell division, autophagic mitochondrial quality control, and execution of apoptosis ( Cook et al, 2017 ; Civenni et al, 2019 ); 3) While showing high degree of autonomy, mitochondria interact with and depend on the cytoskeleton, endoplasmic reticulum, and other cellular structures; 4) Many mitochondrial enzymatic reactions are reversible and can go in either direction which is important for example for the processes of reductive carboxylation and lipid biosynthesis ( Mullen et al, 2011 ; Mullen et al, 2014 ; Nowinski et al, 2020 ); 5) mtDNA has limited ability to repair and, thus, much more vulnerable to damage when compared to nuclear DNA ( Picard et al, 2016 ; Kopinski et al, 2021 ; Singh et al, 2021 ); 6) More active mitochondria are more involved in the execution of apoptosis and, therefore, mitochondrial oxidative metabolism sensitizes cells to cell death ( Whelan et al, 2012 ; Ferranti et al, 2020 ); and 7) Opening of a large non-selective Mitochondrial Permeability Transition Pore (MPTP) controlled by cyclophilin D (CypD) is a convergence point for various pathogenic signals leading to loss of IMM integrity and mitochondrial dysfunction ( Giorgio et al, 2010 ; Bernardi et al, 2015a ; Bernardi et al, 2015b ; Bernardi et al, 2021 ).…”

Protein Transduction Domain-Mediated Delivery of Recombinant Proteins and In Vitro Transcribed mRNAs for Protein Replacement Therapy of Human Severe Genetic Mitochondrial Disorders: The Case of Sco2 Deficiency

“…As these bacteria and their host cells evolved, they developed a co-dependent relationship [ 14 ]. Through evolution, many of the mitochondrial genes either were lost or transferred to nucleus [ 15 ]; thus, the mitochondrial proteome is derived from both mitochondrial and nuclear DNA (nDNA). mtDNA is a highly compact, circular, double-stranded, haploid DNA strand molecule of 16,569 base pairs (bp) in humans, lacking introns and containing 37 genes that encode 13 structural subunits of the OXPHOS system (complexes I, III, IV, and V) and 22 tRNAs necessary for intramitochondrial protein synthesis and the small (12S) and large (16S) ribosomal RNAs (rRNAs) [ 16 ].…”

“…Mitochondrial dysfunction has also been observed in numerous neurodegenerative disorders, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and Friedreich’s ataxia (FRDA); in age-related disorders; in metabolic disorders; as well in traumatic brain injury, ischemic stroke, and in a wide spectrum of human cancers [ 6 , 15 , 29 ].…”

Mitochondrial Neurodegeneration

“…In addition, we will not discuss the role of mitochondria in common neurodegenerative diseases, such as Parkinson’s, Alzheimer’s, and ALS. For these conditions, we refer the reader the literature [ 110 , 111 , 112 ].…”