Mitochondria are subcellular organelles with numerous functions, including energy production through oxidative phosphorylation (OXPHOS), calcium homeostasis, reactive oxygen species production, scavenging, regulation of apoptosis, and activating caspase family of proteases (1, 2). Defects in mitochondrial gene expression can lead to failure of respiratory chain enzymes and ATP synthase, impairing OXPHOS, which is essential for cellular energy production (3). Mitochondrial disorders are complex multisystemic diseases with heterogenous clinical manifestations and can affect every organ and system (2). Mitochondrial diseases are one of the most prevalent inborn errors in metabolism, affecting about every 1 in 5,000 people (4), up to 1 in 200 infants harbor mtDNA mutations (5). Primary mitochondrial disorders have been traditionally defined as resulting from any mutations in mitochondrial DNA (mtDNA) or nuclear DNA (nDNA). The complex relationship between nDNA and mtDNA genomes and more pathogenic variants (6) has generated debate on the definition based on OXPHOS function or mitochondrial structure and function (2). In primary mitochondrial disorders, high energy demand tissues are affected, resulting in neurologic, vision, hearing, neuromuscular, neurodevelopmental, and behavioral abnormalities.

Mitochondrial disorders are primarily of maternal inheritance but can also have autosomal dominant (AD), autosomal recessive (AR), and X-linked inheritance (6). Additionally, heteroplasmy can have varying effects on different family members (5).

Environmental stimuli producing reactive oxygen species (ROS) can affect mitochondrial function and, with stress, trigger energy deficits of a primary mitochondrial disorder (3). Mitochondrial dysfunction can affect DNA, protein, and lipids and has been implicated in type 2 diabetes, obesity, hypertension, and cardiovascular diseases, severe psychiatric neurological disorders, including schizophrenia, bipolar disorder, Alzheimer’s, and Rett Syndrome (7). Diagnosing mitochondrial disorders comes with many challenges: which tissue will provide the best sample, analyzing hundreds of mtDNA and nDNA gene variations, and epigenetic influences that are not fully understood.

Our literature search yielded 277 publications from the above four databases. PubMed returned 168 results, Scopus returned 96 results, ClinicalTrials.gov returned 9 results, and Cochrane Database returned 4 results. Of the 277 total publications, 42 duplicate records were removed. This led to 235 publications being screened with 95 meeting exclusion criteria and 139 meeting inclusion criteria articles. See Figure 1 (flow chart) for more details.

Of the 139 publications included, 72 were identified as reviews where 62 noted mitochondrial dysfunction and 13 included mitochondrial disorders and or dysfunction; 13 were case reports with 5 discussing mitochondrial dysfunction and 7 relating to mitochondrial disorder. 1 case series noting mitochondrial dysfunction; 8 Observational with 5 reported on mitochondrial dysfunction and 2 on mitochondrial disorder; 5 prospective studies contained 3 mitochondrial dysfunction and 2 mitochondrial disorders; 9 retrospective publications were found, 3 of which was mitochondrial dysfunction-related and 5 mitochondrial disorders; 14 case-control studies 11 mentioned dysfunction of the mitochondria while 3 pertained to mitochondrial disorders; 3 randomized clinical trials were found with 3 discussing mitochondrial dysfunction and 0 relating to mitochondrial disorders; 2 in vitro studies both noting mitochondrial dysfunction; 1 meta-analysis mentioning mitochondrial dysfunction; 12 clinical trials where all 12 mentioned mitochondrial dysfunction.

Review of each type of publication with mention of any NDD, neurocognitive disorder and/or psychiatric/behavioral disorder (Intellectual Disability: Mild, Intellectual Disability: Moderate, Intellectual Disability: Severe, Intellectual Disability (Nonspecific), Language Disorder, ASD, ADHD: Hyperactive, Cerebral Palsy, Schizophrenia, PTSD, Major Depressive Disorder: mild (general), Neurocognitive Disorder Possibly Due to Alzheimer, Bipolar disorder (general/nonspecific), Generalized Anxiety Disorder (general), Personality disorders (general/nonspecific), Neurocognitive Disorder Possibly Due to Parkinson’s, OCD, Dementia) is shown in Figure 2 .

Neurodevelopmental disorders mentioned in publications are detailed in Table 3 . Neurocognitive disorders mentioned in publications are detailed in Table 4 and Behavioral/psychiatric disorders mentioned in publications are detailed in Table 5 .

We examined 139 publications on mitochondrial disease/dysfunction that highlighted the role of mitochondrial disease/dysfunction in NDDs and behavioral/psychiatric disorders. Tables 3 and 5 bring to light the lack of new research studying the relationship between mitochondrial dysfunction and NDDs and psychiatric/behavioral disorders. Additionally, the majority of articles were focused on ASD, leading to the question of whether ASD has a stronger correlation to mitochondrial disease or if it has more research funding.

There is limited research exploring mitochondrial diseases, though more common than is currently understood, affecting 1 in 5000 people (4). Without strong clinical suspicion, mitochondrial diseases can be difficult to diagnose due to their heterogeneous presentation and multiorgan system involvement.

The contents of our systematic review search indicated mitochondrial dysfunction/disorder was mentioned in 100 articles investigating ASD. Of the NDDs and behavioral/psychiatric disorders we searched, the preponderance of the articles focused on elucidating the connection between ASD and mitochondrial function.

In a population-based study, 120 children with ASD were studied for potential etiologies. Of the 69 children tested, 11 likely had a mitochondrial etiology. This connection between mitochondrial function and ASD has led to a shift in terminology, classifying ASD based on pathophysiology—”idiopathic ASD” vs. “mitochondrial ASD” (12). Another study showed that up to 16% of individuals with mtDNA deletions, while only 3.3% of the healthy control had mtDNA deletions. The study concluded that mtDNA mutations were statistically more common in patients with ASD compared to controls (18).

As the relationship between ASD and mitochondrial dysfunction becomes clear, the question of pathophysiology must be accounted for. Individuals with ASD frequently have multiorgan comorbidities. These diverse disorders may be accounted for by concomitant mitochondrial dysfunction. If the mitochondria are affected in ASD and cannot produce enough ATP, it naturally follows that high-energy organ systems would be negatively impacted, resulting in comorbidities (32).

Despite the significant amount of research dedicated to ASD and mitochondrial dysfunction, there are gaps in our knowledge. While ASD is classified as an NDD, there is a behavioral component to its presentation, which is unexplored in these articles. In our review, we found the link between behavioral/psychiatric disorders and mitochondrial dysfunction to be vastly uncharted. There were only 131 mentions of all behavioral/psychiatric disorders, some of which are very brief. Conversely, ASD, which is extensively researched, was the main topic of 100 articles, questioning research bias for such correlation between ASD and mitochondrial disease,.

With an annual budget of over $40 billion, the National Institutes of Health (NIH) is the largest single public funder of biomedical and behavioral research in the world (33). Of the NDDs, neurocognitive disorders, and behavioral/psychiatric disorders we found in our systematic investigation, allocation of NIH research funds (from largest to least) were on: Alzheimer’s disease; intellectual and developmental disabilities; ASD; schizophrenia; Parkinson’s disease; anxiety disorders; MDD; bipolar disorder; ADHD, and Tourette’s.

NIH funding of ASD has increased from $118 million in 2008 to $306 million in 2022, while no funding was provided for mitochondrial disorders (34). This research has resulted in standardized screening tools, such as MCHAT-R/F, that allow pediatricians to identify ASD effectively and systematically. The prevalence of ASD is 1/36 (35) in comparison to 1/5000 for mitochondrial disease. Only with more research and improved standardized screening for mitochondrial disease will we truly know if this difference in prevalence is as substantial as it first appears.

In addition to ASD, our search produced 47 mentions of intellectual disability. One study found a link between genetic variation in mtDNA and ID. In this study, individuals with ID presented with motor coordination deficits, attention deficits, epilepsy, heart conditions, and GI disorders. 79% of the genetic variations were identified as SNPs (36). This study also linked mtDNA mutations to ASD, bipolar disorder, schizophrenia, MELAS, LHON, and Leigh Syndrome, among others. This indicates a common mitochondrial denominator between the NDDs and behavioral/psychiatric disorders we are analyzing in this paper.

Our search generated 44 references to language disorders. One article emphasized the importance of creatine in brain functions. Creatine formation involves mitochondria, and creatine is necessary in the expenditure of ATP. Therefore, in cases of mitochondrial disruption of the creatine pathway, individuals present with intellectual and language disorders (37).

This systematic review search yielded 29 mentions of ADHD. ADHD and ASD were found to have several concomitant biological components, including: increased oxidative stress, increased toxic metal burden, decreased methylation, mitochondrial dysfunction, and cerebral hypoperfusion. These shared features indicate mitochondrial dysfunction plays a key role in the development of both conditions (38). Another article investigated the role of parent-of-origin effects (POE) in the development of ADHD. Specifically, situations in which the unequal passing of genetic information affects mitochondrial function. However, no single mechanism of inheritance for ADHD has been identified, leading us to conclude mitochondrial dysfunction regulating the ADHD phenotype (39).

Similarly, in our analysis of behavioral and psychiatric disorders, the bioenergetic deficits seen in the aforementioned NDDs can contribute to the etiology of several psychiatric disorders, such as schizophrenia, MDD, and bipolar I disorder.

A cross-sectional study done with 12 children with mitochondrial disorders, 33% had depressive symptoms, and 50% of these participants had problems with anxiety (40). In a similar study, 36 adults with confirmed mitochondrial disorders found the lifetime prevalence of major depressive disorder is 54%, 17% for bipolar disorder, 11% for generalized anxiety disorder, and 11% for panic disorder. 17% of subjects were at current risk for suicide, and 8% were considered high risk (41). This raises a question about the correlation between mitochondrial function and prevalent psychiatric disorders.

Twenty-nine articles in our review mention schizophrenia and bring forth compelling evidence of mitochondrial involvement in its pathophysiology, the first of which is mitochondrial morphology. Studies have found mitochondrial swelling and hyperplasia in schizophrenic individuals, as well as inconsistent evidence of altered oxidative phosphorylation due to ETC complex dysfunction. Disease inheritance also implicates mitochondrial involvement, as the rates of schizophrenia are higher in female relatives. Studies indicate that the familial risk of developing schizophrenia was significantly higher in family members who shared mtDNA (42).

Similarly, bipolar disorder was only mentioned 11 times in our systematic review. In addition to several mtDNA SNPs found to correlate with bipolar disorder, previous studies have uncovered significant differences in mitochondrial size and distribution in the CNS of bipolar patients when compared with controls (42). Additionally, as evidenced by increased lipid peroxidation and antioxidant enzyme alterations, it is believed there is an overproduction of ROS in bipolar patients (42). A final, albeit inconsistent, finding points towards a shift from oxidative phosphorylation to glycolysis in bipolar individuals. While intriguing, these findings will remain inconclusive without proper investigation (42).

MDD, referenced 19 times in our literature search on mitochondrial disease, has a lifetime prevalence of 5-17%. Research found in all stress models of depression, there was a bioenergetic impairment such as decreased ATP, increased ROS, and/or decreased antioxidant defense. All of which correspond to an underlying mitochondrial dysfunction, making MDD another example of an exceptionally common condition with evidence of mitochondrial involvement that has not been suitably explored (43).

Delving into neurocognitive disorders, our search noted 16 papers connecting Alzheimer’s disease and mitochondrial dysfunction, even theorizing that deficits in mitochondrial function may be the primary event leading to various neurodegenerative disorders, including schizophrenia and Alzheimer’s disease. The leading postulation of Alzheimer’s pathogenesis involves increased oxidative stress due to mitochondrial impairment. One article suggested an accumulation of deletions and point mutations in mtDNA results in the progressive dementia seen in Alzheimer’s disease (44). Specifically, the most frequent deletion of 4977bp in mtDNA contributes to the reduced functionality of 1+ respiratory chain complexes, effectively blocking the ETC and increasing free radical generation. This increase in free radicals leads to more oxidative damage of mtDNA, continuing the cycle of mitochondrial dysfunction (44).

Our literature search disclosed 11 articles on Parkinson’s disease. One such article investigated the role of monoamine oxidases (MAOs) A and B may play in the pathophysiology of Parkinson’s disease. MAOs are critical to the proper functioning of synaptic neurotransmission, but the byproducts of the reaction have neurotoxic potential. This article suggests in cases where these enzymes are overactive, the accumulation of the byproducts could lead to mitochondrial damage and result in the Parkinsonian phenotype (45).

In conclusion, while these conditions may seem disparate in appearance or clinical presentation, they are all connected by an underlying etiology: mitochondrial dysfunction. ASD, due to its generous research funding, appears to have a stronger correlation with mitochondrial dysfunction. However, with the understanding of research bias, it is more likely that these other conditions have the same connection to mitochondrial impairment but lack the funds to fully investigate.

Diagnosing mitochondrial disorders comes with many challenges: which tissue will provide the best sample, analyzing hundreds of mtDNA and nDNA gene variations, and epigenetic influences that are not fully understood. This makes mitochondrial disease difficult to study, as these difficulties indicate it may frequently go undiagnosed.

In addition to diagnostic complications, treatment and prognostic tools also present challenges. On average, people with mitochondrial disease have 16 major medical issues stemming from dysfunctional energy production (46). Even with research still in its early stages, over 350 pathogenic gene variants have been connected to mitochondrial disease (47). This makes a standardized test to detect mitochondrial disease exceptionally complicated.

With advanced diagnostics, novel therapeutics, and individualized research, we may find mitochondrial defects play a major role in all chronic conditions. That is the future required in order to properly identify and treat mitochondrial disease (48).

Given the aforementioned limitations, there is much that requires improvement in order to enhance care of patients with mitochondrial disease. Specifically, more clinical trials and randomized control trials (RCT) are needed. Of the extensive search we conducted, only 12 were clinical trials and 3 were RCT. 72 of the 139 articles we examined were reviews. We need to cultivate interest, encourage new studies, and advance our understanding of mitochondrial disease.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

DP: Writing – review & editing, Writing – original draft. LS: Writing – review & editing, Writing – original draft. JV: Writing – review & editing, Writing – original draft. SD: Writing – review & editing, Writing – original draft. LP: Writing – review & editing, Writing – original draft. AH: Writing – review & editing, Writing – original draft. SK: Writing – review & editing, Writing – original draft.