Page 32 - Read Online

Page 6 Brault et al. J Transl Genet Genom. 2025;9:1-10 https://dx.doi.org/10.20517/jtgg.2024.83

are required to determine the effect of cardiolipin loss on the energetic state in the muscles of individuals
with BTHS. While ATP levels are decreased in some instances, it does seem clear from cell models that
despite a well-described and severe decrement in maximal mitochondrial oxygen consumption/ATP
generating capacity when cardiolipin is reduced, ATP depletion or a decrease in the energetic state is not
obligatory in BTHS. Therefore, despite ongoing pathology, a near-normal energetic status may be
maintained, likely due to cellular compensations such as an increase in mitochondrial number or alternative
pathways. Of course, this assumes that some basal rate of ATP production can be maintained, as if ATP
production is too low to meet basal ATP needs, then ATP levels will rapidly decrease, and the cell will die.

ENERGETIC STATE IN OTHER MITOCHONDRIOPATHIES
To determine whether the lack of a consistent link between mitochondrial ATP production capacity and
cellular ATP content is unique to loss of cardiolipin, we investigated whether other models of
mitochondriopathies showed changes in cellular ATP content. Induced pluripotent stem cell (iPSC)-derived
neurons from patients with DNA polymerase gamma, catalytic subunit (POLG)-related mitochondrial DNA
[85]
depletion syndrome exhibit decreased mitochondrial content and ATP . However, in McArdle’s disease
[86]
patients with different defects in mitochondrial DNA, ATP levels were not different in skeletal muscle . In
a mouse model of Succinate-CoA ligase ADP-forming subunit beta (an enzyme of the TCA cycle) deficiency,
which results in muscle atrophy and muscle weakness in a subset of skeletal muscles, ATP, ADP, and AMP
content are normal in those muscles . In cell models with pathogenic mitochondrial DNA mutations in
[87]
ATP synthase or mitochondrial-null cells, cytosolic levels of ATP measured by luciferase constructs were no
different from wild-type cells . Therefore, while impaired OxPhos is an important mediator of ATP
[88]
production, it is not the sole determinant of steady-state ATP content.

OUTLOOK
BTHS is a devastating genetic condition caused by mutations in TAFAZZIN, which result in limited
capacity for mitochondria to produce ATP from ADP. ATP content varies depending on the energetic state
of the cell, and the specific cell types and organs being examined, as well as temporal disease progression.
Therefore, direct organ-specific measures of ATP are critically important. Many cell models of BTHS and
cells from patients with BTHS demonstrate a decrease in relative ATP amount, but others reveal an increase
or no change. Unfortunately, most of these studies do not provide ADP measures, which makes it
impossible to determine whether the free energy of ATP has indeed been changed or whether the cell/tissue
has undergone a phenotypic change that has remodeled the entire adenine nucleotide pool. Therefore,
measures of ATP are required, but alone are not sufficient to fully understand the energetic state and thus
may limit sweeping interpretations. Further, BTHS and other mitochondrial myopathies are not necessarily
characterized by ATP depletion. It is recommended that a more comprehensive approach be used with
simultaneous measures of ATP, ADP, and AMP.

DECLARATIONS
Authors’ contributions
Conceptualization and drafting of the manuscript, review and editing: Brault JJ, Conway SJ

Availability of data and materials
Not applicable.

Financial support and sponsorship
These studies were supported, in part, by the Allen Family, the Riley Children’s Foundation, and the
National Institutes of Health grant R01 HL159436.